NZ772411A - Crystalline forms of c21h22ci2n4o2 - Google Patents

Crystalline forms of c21h22ci2n4o2

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Publication number
NZ772411A
NZ772411A NZ772411A NZ77241116A NZ772411A NZ 772411 A NZ772411 A NZ 772411A NZ 772411 A NZ772411 A NZ 772411A NZ 77241116 A NZ77241116 A NZ 77241116A NZ 772411 A NZ772411 A NZ 772411A
Authority
NZ
New Zealand
Prior art keywords
formula
crystalline form
compound
xrpd
mixture
Prior art date
Application number
NZ772411A
Inventor
Gary Decrescenzo
Dean Welsch
Petinka I Vlahova
Stephan X M Boerrigter
Alexander Aronov
Ali Keshavarz-Shokri
Alexander N Scangas
Kathy Stavropoulos
Benjamin Littler
Irina Nikolaevna Kadiyala
Rossitza Gueorguieva Alargova
Original Assignee
Vertex Pharma
Biomed Valley Discoveries Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Vertex Pharma, Biomed Valley Discoveries Inc filed Critical Vertex Pharma
Publication of NZ772411A publication Critical patent/NZ772411A/en

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Abstract

The present invention provides crystalline forms of a compound of formula (I). Also provided are pharmaceutical compositions that include the provided crystalline forms and methods of using the provided crystalline forms and pharmaceutical compositions for the treatment of cancer.

Description

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There exists an unmet need for lline forms of 4-(5-Chloro-2— isopropylaminopyridinyl)-1H-pyrroIecarboxylic acid [1—(3—chlorophenyl)-2— hydroxyethyl]amide which exhibit improved ties for formulation of pharmaceutical compositions. The present application is directed to meeting this and other needs.
SUMMARY OF THE INVENTION It has been discovered that crystalline forms of hloro-2— isopropylaminopyridinyl)-1H-pyrrole-2—carboxylic acid [1 -(3-chlorophenyl)-2— hydroxyethyl]amide can be prepared which exhibit improved properties, e.g. surprisingly improved stability and improved solubility characteristics.
Thus, the present invention provides lline 4—(5—Chloro-2— isopropylaminopyridinyl)-1H-pyrroIe-2—carboxylic acid [1 -(3-chloropheny|)-2— hydroxyethyl]amide.
The present invention also es crystalline free base 4-(5-Chloro-2— pylaminopyridin—4—yl)—1H—pyrroIe—2—carboxylic acid [1—(3—chloropheny|)—2— hydroxyethyl]amide.
The present invention also provides a crystalline free base of a compound of formula: having an X—ray powder diffraction (XRPD) pattern comprising a characteristic peak at about 195° 26.
The present invention also provides a crystalline free base of a compound of formula: having an XRPD pattern comprising characteristic peaks at about 9.1 and 195° 26.
The present ion also provides a crystalline free base of a compound of formula: having an XRPD pattern comprising characteristic peaks at about 9.1, 15.4, 19.5 and 21.4° 26.
The present invention also provides a crystalline free base of a compound of formula: having one or more XRPD lections (°) selected from the group consisting of about 9.1, 12.5, 15.2, 15.4, 19.2, 19.5, 20.3, 20.5, 21.4, 21.7, 21.9, 23.1, 23.3, 23.6, and 24.3.
The present invention also provides a crystalline free base of a compound of formula: having an XRPD pattern substantially as shown in The present invention also provides pharmaceutical itions comprising any of the crystalline compounds of the present invention.
The present invention also provides a method of treating a cancer in a subject in need f comprising administering to the subject an effective amount of any of the crystalline compounds of the t invention.
The present ion also provides a method of treating a cancer in a t in need thereof comprising administering to the subject an effective amount of any of the pharmaceutical compositions of the present invention.
The present invention also provides crystalline 4-(5-Chloro-2— isopropylaminopyridinyl)-1H-pyrroIecarboxylic acid [1—(3—chloropheny|) hydroxyethy|]amide mono HCI.
The present invention also provides a crystalline hydrochloride salt of a compound of formula: having an X—ray powder ction (XRPD) pattern comprising a characteristic peak at about 67° 26.
The present invention also provides a crystalline hydrochloride salt of a compound of formula: having an XRPD n comprising characteristic peaks at about 6.7 and 110° 26.
The present invention also provides a crystalline hydrochloride salt of a compound of a: having an XRPD pattern comprising characteristic peaks at about 6.7, 11.0, 17.6 and 199° 26.
The present invention also provides a crystalline hydrochloride salt of a compound of formula: having one or more XRPD 29-reflections (°) selected from the group consisting of about 6.1, 6.7, 11.0, 12.1, 13.7, 15.2, 16.5, 17.6, 17.9, 18.4, 18.7, 19.6, 19.9, and .4.
The present invention also provides a crystalline hydrochloride salt of a compound of formula: having an XRPD pattern substantially as shown in The present invention also provides crystalline hloro isopropylaminopyridin—4—yl)—1H—pyrroIe—2—carboxylic acid [1—(3—chloropheny|)—2— hydroxyethy|]amide HCI hydrate.
The present invention also provides a lline hydrochloride salt of a compound of formula: having an X-ray powder diffraction (XRPD) pattern comprising a characteristic peak at about 105° 26.
The present invention also es a crystalline hloride salt of a compound of formula: having an XRPD pattern comprising characteristic peaks at about 6.2 and 105° 26.
The present invention also provides a crystalline hydrochloride salt of a compound of formula: having an XRPD pattern comprising characteristic peaks at about 6.2, 10.5, 22.4 and 28.5° 29.
The present invention also provides a crystalline hydrochloride salt of a compound of formula: having one or more XRPD 26-reflections (°) selected from the group consisting of about 5.8, 5.9, 6.2, 10.5, 11.8, 12.4, 15.9, 17.6, 17.8, 20.0, 20.4, 21.1, 21.4, 21.9, 22.4, 23.1, 24.0, 24.2, 24.9, and 25.3.
The t invention also provides a crystalline hydrochloride salt of a compound of formula: having an XRPD pattern substantially as shown in The present invention also es a crystalline hydrochloride salt of a nd of formula: having an X-ray powder diffraction (XRPD) pattern comprising a teristic peak at about 10.7° 26.
The t invention also provides a crystalline hydrochloride salt of a compound of formula: having an XRPD pattern comprising characteristic peaks at about 10.7 and 181° 26.
The present invention also provides a crystalline hydrochloride salt of a compound of formula: WO 23574 PCT/USZOl6/015829 having an XRPD pattern comprising characteristic peaks at about 6.0, 10.7, 12.7, and 181° 29.
The t invention also provides a crystalline hydrochloride salt of a compound of formula: having one or more XRPD 26-reflections (°) selected from the group consisting of about 6.0, 6.3, 10.7, 12.0, 12.7, 15.6, 16.2, 16.3, 16.7, 17.9, 18.1, and 21.4.
The present invention also provides a crystalline hydrochloride salt of a compound of formula: having an XRPD pattern ntially as shown in .
BRIEF DESCRIPTION OF THE DRAWINGS The following drawings form part of the present specification and are included to further demonstrate certain aspects of the present invention. The WO 23574 PCT/U82016/015829 invention may be better understood by reference to one or more of these drawings in combination with the ed description of specific embodiments presented herein. shows the XRPD of 4—(5—ChIoroisopropylaminopyridin—4—yl)— 1H-pyrroIecarboxylic acid chIorophenyI)hydroxyethyl]amide free base acquired in transmission mode. shows the FT-IR spectrum of 4-(5-Chloro-2— isopropylaminopyridin—4—yI)—1H—pyrroIe—2—carboxylic acid [1—(3—chlorophenyI)—2— hydroxyethyl]amide free base. shows the DSC thermogram of 4—(5—Chloro—2— isopropylaminopyridinyI)-1H-pyrroIecarboxylic acid [1 -(3-ch|orophenyI) hydroxyethyl]amide free base. shows the XRPD of 4-(5-ChIoroisopropylaminopyridiny|)- 1H-pyrroIecarboxylic acid [1-(3-ch|oropheny|)hydroxyethy|]amide Form C acquired in transmission mode. shows the FT—IR spectrum of 4-(5-Chloro-2— isopropylaminopyridinyI)-1H-pyrroIecarboxylic acid [1 -(3-ch|orophenyI) hydroxyethyl]amide Form C. shows the DSC thermogram of 4-(5-Chloro-2— isopropylaminopyridinyI)-1H—pyrroIe—2—carboxylic acid [1 -(3-ch|orophenyI) hydroxyethyl]amide Form C. shows the XRPD of 4-(5-ChIoroisopropylaminopyridiny|)- 1H-pyrrole-2—carboxylic acid [1-(3-ch|oropheny|)—2—hydroxyethy|]amide Form A acquired in transmission mode. shows the FT—IR spectrum of 4—(5—Chloro-2— isopropylaminopyridinyl)-1H-pyrrole-2—carboxylic acid [1 -(3-chlorophenyI) yethyl]amide Form A. shows the DSC thermogram of 4-(5-Chloro-2— isopropylaminopyridin—4—yl)—1H—pyrrole—2—carboxylic acid [1—(3—chlorophenyl)—2— hydroxyethyl]amide Form A. shows the XRPD of 4—(5—Chloro—2—isopropylaminopyridin—4—yl)— 1H-pyrrole-2—carboxylic acid [1-(3-chIorophenyl)-2—hydroxyethyl]amide Form D acquired in reflection mode. shows the FT-IR spectrum of 4-(5-Chloro-2— isopropylaminopyridin—4—yl)—1H—pyrrole—2—carboxylic acid [1—(3—chlorophenyI)—2— yethyl]amide Form D. shows the DSC thermogram of 4-(5-Chloro-2— isopropylaminopyridinyl)-1H-pyrroIecarboxylic acid [1 -(3-chlorophenyI) hydroxyethyl]amide Form D. shows a comparison of the Raman spectra from 1000 — 1600 cm'1 for 4—(5—ChIoroisopropylaminopyridin—4—yl)-1H-pyrrole—2—carboxylic acid [1—(3— chIorophenyl)hydroxyethyl]amide Forms A and C. shows a comparison of the Raman spectra from 950 — 1030 cm"1 for 4-(5-ChIoroisopropylaminopyridinyI)-1H-pyrroIecarboxylic acid [1-(3- phenyl)hydroxyethyl]amide Forms A and C.
ED DESCRIPTION OF THE INVENTION The present invention provides crystalline 4-(5-Chloro-2— isopropylaminopyridinyl)-1H—pyrrole—2—carboxylic acid [1 -(3-chlorophenyl) hydroxyethyl]am ide.
The present invention also provides crystalline free base 4—(5—Chloro-2— isopropylaminopyridinyl)-1H-pyrrole-2—carboxylic acid [1 -(3-chlorophenyl) hydroxyethyl]amide.
The present invention also provides a crystalline free base of a compound of formula: having an X-ray powder diffraction (XRPD) pattern comprising a characteristic peak at about 195° 26.
The present invention also provides a crystalline free base of a nd of a: having an XRPD pattern sing characteristic peaks at about 9.1 and 196° 29.
The present invention also provides a crystalline free base of a compound of formula: having an XRPD n comprising characteristic peaks at about 9.1, 15.4, 19.5 and 21.4° 26.
The present invention also provides a crystalline free base of a compound of formula: having one or more XRPD 29—reflections (°) selected from the group consisting of about 9.1, 12.5, 15.2, 15.4, 19.2, 19.5, 20.3, 20.5, 21.4, 21.7, 21.9, 23.1, 23.3, 23.6, and 24.3.
The t invention also provides a crystalline free base of a compound of formula: having an XRPD pattern substantially as shown in The present invention also provides crystalline free base hloro-2— isopropylaminopyridinyI)-1H-pyrroIecarboxylic acid [1 -(3-ch|oropheny|)-2— hydroxyethy|]amide mono HCI having a Fourier transform infrared spectroscopy (FT- IR) spectrum comprising one or more peaks at about 1603, 1533, 1487, 1080, 857, and 681 cm'1.
The present invention also provides crystalline free base hloro-2— isopropylaminopyridinyl)-1H-pyrroIe-2—carboxylic acid [1 -(3-chloropheny|) hydroxyethy|]amide mono HCI having an FT—IR spectrum substantially as shown in The present invention also provides crystalline free base4—(5—Chloro-2— isopropylaminopyridinyl)-1H-pyrroIecarboxylic acid [1 -(3-ch|oropheny|)-2— yethy|]amide mono HCI having (i) an XRPD pattern comprising one or more peaks at about 9.1, 15.4, 19.5 and 21.4° 29; and (ii) a FT-IR spectrum comprising one or more peaks at about 1603, 1533, 1487, 1080, 857, and 681 cm'1.
The t invention also provides lline free base 4-(5-Chloro-2— isopropylaminopyridin—4—yI)—1H—pyrroIe—2—carboxylic acid [1—(3—chlorophenyI)—2— hydroxyethy|]amide mono HCI having a DSC thermogram with an endotherm having an onset temperature of approximately 184°C.
The t invention also provides crystalline free base 4—(5—Chloro-2— isopropylaminopyridinyl)-1H-pyrrole-2—carboxylic acid [1 -(3-chlorophenyl) hydroxyethyl]amide mono HCl having a DSC thermogram substantially as shown in The present invention also es a pharmaceutical composition comprising a crystalline compound of the present invention.
The present invention also provides a method of treating a cancer in a subject in need f comprising administering to the subject an effective amount of a crystalline compound of the present invention.
In some embodiments, the subject is a mammal.
In some embodiments, the mammal is selected from the group consisting of humans, primates, farm animals, and domestic animals.
In some ments, the mammal is a human.
In some embodiments, the method further comprises stering to the subject at least one additional anti-cancer agent.
The present invention also provides a method of treating a cancer in a t in need thereof comprising administering to the subject an effective amount of a pharmaceutical composition of the present invention.
In some embodiments, the subject is a mammal.
In some embodiments, the mammal is selected from the group consisting of humans, primates, farm animals, and domestic animals.
In some ments, the mammal is a human.
In some embodiments, the method further comprises administering to the subject at least one onal anti-cancer agent.
The present invention also provides crystalline hloro-2— isopropylaminopyridinyl)-1H-pyrroIe-2—carboxylic acid [1 lorophenyl) hydroxyethy|]amide mono HCI.
The present invention also provides a lline hydrochloride salt of a compound of formula: having an X-ray powder diffraction (XRPD) pattern comprising a characteristic peak at about 67° 26.
The present invention also provides a crystalline hydrochloride salt of a compound of formula: having an XRPD pattern comprising characteristic peaks at about 6.7 and 110° 29.
The present invention also provides a crystalline hydrochloride salt of a compound of formula: having an XRPD n comprising characteristic peaks at about 6.7, 11.0, 17.6 and 199° 26.
The present ion also provides a crystalline hydrochloride salt of a compound of formula: having one or more XRPD 29—reflections (°) selected from the group consisting of about 6.1, 6.7, 11.0, 12.1, 13.7, 15.2, 16.5, 17.6, 17.9, 18.4, 18.7, 19.6, 19.9, and .4.
The present invention also provides a crystalline hydrochloride salt of a compound of formula: WO 23574 having an XRPD pattern substantially as shown in The present invention also provides form C crystalline 4-(5-Chloro isopropylaminopyridinyI)-1H-pyrroIe-2—carboxylic acid [1-(3-chlorophenyI) hydroxyethyl]amide mono HCI having a Fourier transform infrared spectroscopy (FT- IR) spectrum comprising one or more peaks at about 1610, 1523, 1219, 1141, 1076, and 845 cm‘1.
The present invention also provides form C crystalline hloro-2— isopropylaminopyridinyl)-1H-pyrrolecarboxylic acid [1 -(3-chlorophenyl) hydroxyethyl]amide mono HCI having an FT—IR spectrum substantially as shown in The present invention also es form C lline 4-(5-Chloro isopropylaminopyridinyI)—1H-pyrrolecarboxylic acid [1—(3—chlorophenyl) hydroxyethyl]amide mono HCI having (i) an XRPD pattern comprising one or more peaks at about 6.7, 11.0, 17.6, and 199° 26; and (ii) a FT-IR spectrum comprising one or more peaks at about 1610, 1523, 1219, 1141, 1076, and 845 cm'1.
The present invention also provides form C crystalline 4—(5—Chloro isopropylaminopyridinyl)-1H-pyrrolecarboxylic acid [1 -(3-chlorophenyl) hydroxyethyl]amide mono HCI having a DSC thermogram with an endotherm having an onset temperature of approximately 239°C.
The t invention also provides form C lline 4—(5—Chloro-2— isopropylaminopyridinyI)-1H-pyrroIe-2—carboxylic acid [1 -(3-chlorophenyI) hydroxyethy|]amide mono HCI having a DSC thermogram substantially as shown in The present invention also provides a pharmaceutical composition sing a crystalline compound of the present invention.
The present ion also provides a method of treating a cancer in a subject in need thereof comprising administering to the subject an effective amount of a crystalline nd of the present invention.
In some embodiments, the subject is a mammal.
In some embodiments, the mammal is selected from the group consisting of , primates, farm animals, and domestic animals.
In some embodiments, the mammal is a human.
In some embodiments, the method further comprises administering to the subject at least one additional ancer agent.
The present invention also provides a method of treating a cancer in a subject in need thereof comprising administering to the subject an effective amount of a pharmaceutical composition of the present invention.
In some embodiments, the subject is a mammal.
In some embodiments, the mammal is selected from the group consisting of humans, primates, farm animals, and domestic animals.
In some embodiments, the mammal is a human.
In some ments, the method further comprises administering to the subject at least one additional anti-cancer agent.
The present invention also provides crystalline 4—(5—Chloro-2— pylaminopyridinyl)-1H-pyrroIe-2—carboxylic acid [1 -(3-chlorophenyl) hydroxyethy|]amide HCI hydrate.
The present invention also provides a crystalline hydrochloride salt of a compound of formula: having an X-ray powder diffraction (XRPD) pattern sing a characteristic peak at about 105° 26.
The present invention also provides a crystalline hydrochloride salt of a compound of formula: having an XRPD pattern comprising characteristic peaks at about 6.2 and 105° 29.
The present invention also es a crystalline hydrochloride salt of a compound of formula: having an XRPD pattern comprising characteristic peaks at about 6.2, 10.5, 22.4 and 28.5° 29.
The present invention also provides a crystalline hydrochloride salt of a nd of formula: having one or more XRPD 29—reflections (°) selected from the group consisting of about 5.8, 5.9, 6.2, 10.5, 11.8, 12.4, 15.9, 17.6, 17.8, 20.0, 20.4, 21.1, 21.4, 21.9, 22.4, 23.1, 24.0, 24.2, 24.9, and 25.3.
The present invention also provides a crystalline hydrochloride salt of a nd of formula: having an XRPD pattern ntially as shown in The present invention also provides form A crystalline 4-(5-Chloro isopropylaminopyridiny|)-1H-pyrroIe-2—carboxylic acid [1-(3-chlorophenyI) hydroxyethyl]amide HCI hydrate having a r transform infrared spectroscopy (FT—IR) spectrum comprising one or more peaks at about 1573, 1237, 1163, 946, and 790 cm‘1.
The present invention also provides form A crystalline 4-(5-Chloro-2— isopropylaminopyridinyl)-1H-pyrrolecarboxylic acid [1 -(3-chlorophenyl) hydroxyethyl]amide HCI hydrate having an FT-IR spectrum substantially as shown in The present invention also provides form A crystalline 4-(5-Chloro pylaminopyridinyI)—1H-pyrrolecarboxylic acid [1—(3—chlorophenyl) hydroxyethyl]amide HCI hydrate having (i) an XRPD n comprising one or more peaks at about 6.2, 10.5, 22.4, and 285° 26; and (ii) a FT-IR spectrum comprising one or more peaks at about 1573, 1237, 1163, 946, and 790 cm'1.
The present invention also provides form A crystalline 4—(5—Chloro isopropylaminopyridinyl)-1H-pyrrolecarboxylic acid [1 -(3-chlorophenyl) yethyl]amide HCI hydrate having a D80 thermogram substantially as shown in The present invention also provides a pharmaceutical composition comprising a crystalline compound of the present ion.
The present invention also provides a method of treating a cancer in a subject in need thereof comprising administering to the subject an effective amount of a crystalline compound of the present invention.
In some embodiments, the t is a mammal.
In some embodiments, the mammal is selected from the group consisting of humans, primates, farm animals, and domestic animals.
In some embodiments, the mammal is a human.
In some embodiments, the method further comprises administering to the subject at least one additional anti—cancer agent.
The present invention also provides a method of treating a cancer in a subject in need thereof comprising administering to the subject an effective amount of a ceutical composition of the present invention.
In some ments, the subject is a mammal.
In some embodiments, the mammal is selected from the group consisting of humans, primates, farm s, and domestic animals.
In some embodiments, the mammal is a human.
In some ments, the method further comprises stering to the subject at least one additional anti-cancer agent.
The present invention also provides a crystalline hydrochloride salt of a compound of formula: having an X-ray powder diffraction (XRPD) pattern comprising a characteristic peak at about 10.7° 26.
The present ion also provides a crystalline hydrochloride salt of a compound of formula: having an XRPD pattern comprising characteristic peaks at about 10.7 and 181° 26.
The present invention also provides a crystalline hydrochloride salt of a nd of formula: having an XRPD pattern comprising characteristic peaks at about 6.0, 10.7, 12.7, and 181° 29.
The present invention also provides a crystalline hydrochloride salt of a nd of formula: having one or more XRPD 26-reflections (°) selected from the group consisting of about 6.0, 6.3, 10.7, 12.0, 12.7, 15.6, 16.2, 16.3, 16.7, 17.9, 18.1, and 21.4.
The present invention also es a crystalline hydrochloride salt of a compound of formula: having an XRPD pattern substantially as shown in .
The present invention also provides form D crystalline 4-(5-Chloro isopropylaminopyridinyl)—1H-pyrroIecarboxylic acid [1—(3—chloropheny|) hydroxyethy|]amide HCI having a Fourier transform infrared spectroscopy (FT-IR) spectrum comprising one or more peaks at about 1537, 1471, 1239, 1163, 1067, and 946 cm'1.
The present invention also provides form D crystalline 4—(5—Chloro isopropylaminopyridinyl)-1H-pyrroIecarboxylic acid [1 -(3-chloropheny|) hydroxyethyl]amide HCI having an FT—IR spectrum substantially as shown in FIG.
The present invention also provides form D lline 4—(5—Chloro—2— isopropylaminopyridinyl)-1H-pyrrolecarboxylic acid [1 -(3-chloropheny|) yethyl]amide HCI having (i) an XRPD pattern comprising one or more peaks at about 6.0, 12.7, and 181° 26; and (ii) a FT-IR spectrum comprising one or more peaks at about 1537, 1471, 1239, 1163, 1067, and 946 cm'1.
The present invention also provides form D crystalline 4-(5-Chloro isopropylaminopyridiny|)-1H-pyrroIe-2—carboxylic acid [1-(3-chloropheny|) hydroxyethyl]amide HCI having a D80 thermogram substantially as shown in FIG.
The t invention also provides a ceutical composition comprising a crystalline compound of the present invention.
The present invention also provides a method of treating a cancer in a subject in need thereof comprising administering to the subject an effective amount of a crystalline compound of the present ion.
In some embodiments, the subject is a mammal.
In some ments, the mammal is selected from the group consisting of humans, primates, farm animals, and domestic animals.
In some embodiments, the mammal is a human.
In some embodiments, the method further comprises administering to the subject at least one additional anti-cancer agent.
The present ion also provides a method of treating a cancer in a subject in need thereof sing administering to the t an effective amount of a pharmaceutical composition of the present invention.
In some embodiments, the subject is a mammal.
In some ments, the mammal is selected from the group consisting of humans, primates, farm animals, and domestic animals.
In some embodiments, the mammal is a human.
In some ments, the method further comprises administering to the subject at least one additional anti—cancer agent.
The term "solid form" is often used to refer to a class or type of solid- state material. One kind of solid form is a "polymorph" which refers to two or more compounds having the same chemical formula but differing in solid-state structure.
Salts may be polymorphic. When polymorphs are elements, they are termed allotropes. Carbon possesses the nown allotropes of graphite, diamond, and nsterfullerene. Polymorphs of molecular compounds, such as active pharmaceutical ingredients ("APIs"), are often prepared and studied in order to identify compounds meeting scientific or commercial needs including, but not limited to, improved solubility, dissolution rate, copicity, and stability.
Other solid forms include solvates and es of compounds including salts. A solvate is a compound wherein a solvent molecule is present in the crystal structure together with another compound, such as an API. When the solvent is water, the solvent is termed a hydrate. es and hydrates may be stoichiometric or non-stoichiometric. A monohydrate is the term used when there is one water molecule, stoichiometrically, with respect to, for example, an API, in the unit cell.
In order to identify the presence of a particular solid form, one of ordinary skill typically uses a suitable analytical que to collect data on the form for analysis. For example, chemical identity of solid forms can often be determined with solution-state techniques such as 13C-NMR or 1H-NMR spectroscopy and such techniques may also be valuable in determining the iometry and presence of "guests" such as water or solvent in a hydrate or solvate, respectively. These spectroscopic techniques may also be used to distinguish, for e, solid forms without water or solvent in the unit cell (often referred to as "anhydrates"), from hydrates or solvates.
Solution-state ical techniques do not provide information about the solid state as a substance and thus, for example, solid-state techniques may be used to distinguish among solid forms such as anhydrates. Examples of solid-state techniques which may be used to analyze and characterize solid forms, including anhydrates and es, e single crystal X-ray diffraction, X-ray powder diffraction ("XRPD"), solid-state 13C-NMR, Infrared ("IR") spectroscopy, including Fourier Transform Infrared (FT-IR) spectroscopy, Raman oscopy, and thermal techniques such as Differential Scanning calorimetry (DSC), melting point, and hot stage microscopy.
Polymorphs are a subset of lline forms that share the same chemical structure but differ in how the molecules are packed in a solid. When attempting to guish polymorphs based on analytical data, one looks for data which terize the form. For example, when there are two polymorphs of a compound (e.g., Form | and Form ll), one can use X-ray powder diffraction peaks to characterize the forms when one finds a peak in a Form | pattern at angles where no such peak is t in the Form || pattern. In such a case, that single peak for Form | guishes it from Form II and may further act to characterize Form |. When more forms are present, then the same analysis is also done for the other polymorphs.
Thus, to terize Form | against the other polymorphs, one would look for peaks in Form | at angles where such peaks are not present in the X—ray powder diffraction patterns of the other polymorphs. The collection of peaks, or indeed a single peak, which distinguishes Form I from the other known polymorphs is a collection of peaks which may be used to characterize Form |. If, for example, two peaks characterize a polymorph then those two peaks can be used to identify the presence of that polymorph and hence characterize the polymorph. Those of ry skill in the art will recognize that there are often multiple ways, including multiple ways using the same analytical technique, to characterize polymorphic rphs. For example, one may find that three X-ray powder diffraction peaks characterize a polymorph.
Additional peaks could also be used, but are not necessary, to terize the rph up to and including an entire diffraction pattern. Although all the peaks within an entire diffractogram may be used to characterize a lline form, one may instead, and typically does as disclosed herein, use a subset of that data to characterize such a crystalline form depending on the circumstances.
For example, as used herein, "characteristic peaks" are a subset of observed peaks and are used to differentiate one crystalline polymorph from another crystalline polymorph. Characteristic peaks are determined by evaluating which observed peaks, if any, are present in one crystalline polymorph of a compound against all other known crystalline polymorphs of that compound to within 102° 26.
When analyzing data to guish an anhydrate from a hydrate, for example, one can rely on the fact that the two solid forms have different chemical structures--one having water in the unit cell and the other not. Thus, this feature alone may be used to distinguish the forms of the compound and it may not be necessary to identify peaks in the anhydrate, for example, which are not present in the hydrate or vice versa.
X—ray powder diffraction patterns are some of the most commonly used solid-state analytical techniques used to terize solid forms. An X-ray powder diffraction n is an x-y graph with the diffraction angle, 26 (°), on the x-axis and intensity on the y-axis. The peaks within this plot may be used to characterize a crystalline solid form. The data is often ented by the position of the peaks on the x-axis rather than the intensity of peaks on the y-axis because peak intensity can be particularly sensitive to sample orientation (see Pharmaceutical Analysis, Lee & Web, pp. 255-257 (2003)). Thus, intensity is not typically used by those skilled in the art to characterize solid forms.
As with any data measurement, there is variability in X-ray powder diffraction data. In addition to the ility in peak intensity, there is also ility in the position of peaks on the x-axis. This variability can, however, typically be accounted for when reporting the positions of peaks for purposes of characterization.
Such variability in the position of peaks along the x-axis derives from several sources. One comes from sample preparation. Samples of the same crystalline material, prepared under different conditions may yield slightly different diffractograms. Factors such as particle size, moisture t, solvent content, and orientation may all affect how a sample diffracts . Another source of variability comes from ment parameters. Different X-ray instruments operate using different parameters and these may lead to slightly different diffraction patterns from the same crystalline solid form. Likewise, different software packages process X-ray data differently and this also leads to ility. These and other sources of variability are known to those of ordinary skill in the pharmaceutical arts.
Due to such sources of variability, it is common to recite X—ray diffraction peaks using the word "about" prior to the peak value in degrees (29) (sometimes expressed herein as flections (°)"), which presents the data to within 0.1 or 02° (26) of the stated peak value depending on the circumstances. The X—ray powder diffraction data corresponding to the solid forms of the present invention were collected on instruments which were routinely calibrated and ed by d scientists. In the present invention, XRPD values are preferably ed using Cu Kd X-ray radiation according to the method described in Example 1. Accordingly, the variability associated with these data would be expected to be closer to i0.’l °29 than to :02 °29 and indeed likely less than 0.1 with the instruments used herein. However, to take into account that instruments used elsewhere by those of ordinary skill in the art may not be so maintained, for e, all X-ray powder diffraction peaks cited herein have been reported with a variability on the order of 10.2 °26 and are intended to be reported with such a variability whenever disclosed herein and are reported in the specification to one significant figure after the decimal even though ical output may suggest higher precision on its face.
Single-crystal X-ray diffraction provides three-dimensional structural ation about the positions of atoms and bonds in a crystal. It is not always possible or feasible, however, to obtain such a structure from a crystal, due to, for example, insufficient crystal size or difficulty in preparing crystals of ient y for single-crystal X-ray diffraction.
X—ray powder diffraction data may also be used, in some circumstances, to ine the llographic unit cell of the crystalline structure.
The method by which this is done is called "indexing." ng is the process of determining the size and shape of the crystallographic unit cell consistent with the peak positions in a suitable X—ray powder diffraction pattern. Indexing provides solutions for the three unit cell lengths (a, b, c), three unit cell angles (or, B, y), and three Miller index labels (h, k, I) for each peak. The lengths are typically reported in Angstrom units and the angles in degree units. The Miller index labels are unitless integers. Successful indexing indicates that the sample is composed of one crystalline phase and is therefore not a mixture of crystalline phases.
IR spectroscopy, particularly FT-IR, is another technique that may be used to characterize solid forms together with or separately from X-ray powder diffraction. In an IR spectrum, ed light is plotted on the x-axis of a graph in the units of "wavenumber" (cm‘1), with intensity on the y-axis. Variation in the position of IR peaks also exists and may be due to sample conditions as well as data collection and processing. The typical variability in IR spectra reported herein is on the order of plus or minus 2.0 cm'1. Thus, the use of the word "about" when referencing IR peaks is meant to include this variability and all IR peaks disclosed herein are intended to be reported with such variability. l methods are another l technique to characterize solid forms. Different polymorphs of the same nd often melt at different temperatures. Thus, the melting point of a polymorph, as measured by methods such as capillary melting point, DSC, and hot stage microscopy, alone or in ation with techniques such as X-ray powder diffraction, IR spectroscopy, ing FT-IR, or both, may be used to characterize polymorphs or other solid forms.
As with any analytical technique, melting point determinations are also subject to variability. Common sources of variability, in addition to instrumental ility, are due to colligative properties such as the presence of other solid forms or other impurities within a sample whose melting point is being measured.
As used herein, the terms "treat," ing," "treatment" and grammatical variations thereof mean subjecting an individual subject to a protocol, regimen, process or remedy, in which it is desired to obtain a physiologic response or outcome in that subject, e.g., a patient. In particular, the methods and compositions of the present invention may be used to slow the development of disease ms or delay the onset of the disease or condition, or halt the progression of e development. However, because every treated subject may not respond to a particular treatment protocol, n, process or remedy, ng does not require that the desired physiologic response or outcome be achieved in each and every subject or subject population, e.g., patient population. Accordingly, a given t or subject tion, e.g., patient population may fail to respond or respond inadequately to treatment.
As used herein, the terms "ameliorate", "ameliorating" and grammatical variations thereof mean to decrease the severity of the symptoms of a e in a As used herein, a "subject" is a mammal, preferably, a human. In addition to humans, categories of mammals within the scope of the present invention include, for example, farm animals, domestic animals, laboratory animals, etc. Some examples of farm animals e cows, pigs, horses, goats, etc. Some examples of domestic animals include dogs, cats, etc. Some examples of laboratory animals include primates, rats, mice, rabbits, guinea pigs, etc.
Cancers include both solid and hemotologic cancers. Non-limiting examples of solid s e adrenocortical carcinoma, anal cancer, bladder cancer, bone cancer (such as osteosarcoma), brain cancer, breast cancer, carcinoid cancer, carcinoma, cervical cancer, colon cancer, endometrial cancer, esophageal cancer, extrahepatic bile duct cancer, Ewing family of cancers, extracranial germ cell cancer, eye cancer, gallbladder cancer, gastric cancer, germ cell tumor, gestational trophoblastic tumor, head and neck cancer, aryngeal , islet cell carcinoma, kidney cancer, large intestine cancer, laryngeal cancer, leukemia, lip and oral cavity cancer, liver cancer, lung cancer, lymphoma, malignant mesothelioma, Merkel cell carcinoma, mycosis fungoides, myelodysplastic syndrome, myeloproliferative ers, nasopharyngeal cancer, neuroblastoma, oral cancer, oropharyngeal cancer, osteosarcoma, ovarian epithelial cancer, ovarian germ cell cancer, pancreatic cancer, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pituitary , plasma cell neoplasm, prostate cancer, rhabdomyosarcoma, rectal cancer, renal cell cancer, transitional cell cancer of the renal pelvis and ureter, salivary gland cancer, Sézary syndrome, skin cancers (such as cutaneous t-cell lymphoma, Kaposi's sarcoma, mast cell tumor,and melanoma), small intestine cancer, soft tissue sarcoma, stomach , testicular , thymoma, d cancer, urethral cancer, e cancer, vaginal , vulvar cancer, and Wilms' tumor.
Examples of hematologic cancers include, but are not d to, leukemias, such as adult/childhood acute blastic leukemia, adult/childhood acute myeloid leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia, lymphomas, such as elated lymphoma, ous T—cell lymphoma, adult/childhood Hodgkin lymphoma, mycosis fungoides, adult/childhood non-Hodgkin lymphoma, primary central nervous system lymphoma, Sézary syndrome, cutaneous T—cell lymphoma, and Waldenstrom macroglobulinemia, as well as other proliferative disorders such as chronic roliferative disorders, Langerhans cell histiocytosis, le myeloma/plasma cell neoplasm, ysplastic syndromes, and myelodysplastic/myeloproliferative neoplasms. A preferred set of cancers that may be treated according to the present invention include neuroblastoma, leukemia, lymphoma, liver cancer, lung cancer, skin , testicular cancer, and thyroid cancer. Preferably, the cancer is melanoma.
The methods of the present ion may optionally further include administering to the subject at least one additional therapeutic agent effective for treating or ameliorating the effects of the cancer. The additional therapeutic agent may be selected from the group consisting of an antibody or fragment thereof, a chemotherapeutic agent, an immunotherapeutic agent, a radionuclide, a photoactive therapeutic agent, a radiosensitizing agent, and ations thereof.
The crystalline, free base, and salt forms of 4-(5-Chloro-2— pylaminopyridinyl)-1H-pyrrolecarboxylic acid [1 -(3-chlorophenyl)-2— hydroxyethyl]amide (hereinafter "solid forms of the present invention") and the anti- cancer agent(s) used in the co-treatment therapy may be administered to the subject, either simultaneously or at different times, as deemed most riate. If the solid forms of the present invention and the other anti-cancer agent(s) are administered at different times, for example, by serial administration, then the solid forms of the present invention may be administered to the subject before the other anti-cancer agent. Alternatively, the other anti-cancer agent(s) may be administered to the subject before the 4—(5-Chloroisopropylaminopyridin-4—y|)—1H-pyrrole carboxylic acid [1 —(3—chlorophenyl)hydroxyethy|]amide.
As used herein, an "antibody" encompasses naturally ing immunoglobulins as well as non-naturally occurring immunoglobulins, including, for example, single chain antibodies, chimeric antibodies (e.g., humanized murine antibodies), and heteroconjugate antibodies (e.g., bispecific antibodies). Fragments of antibodies include those that bind antigen, (e.g., Fab', F(ab')2, Fab, Fv, and rlgG).
See also, e.g., Pierce Catalog and Handbook, 1994-1995 (Pierce Chemical Co., Rockford, Ill); Kuby, J., Immunology, 3rd Ed., W.H. n & Co., New York (1998). The term antibody also includes bivalent or bispecific molecules, diabodies, triabodies, and tetrabodies. The term "antibody" r es both polyclonal and onal antibodies. es of therapeutic antibodies that may be used in the present invention include rituximab (Rituxan), Cetuximab (Erbitux), zumab (Avastin), and lbritumomab (Zevalin).
As used herein, "chemotherapeutic agent" means any eutic agent that is ible with the solid forms of the present inventiontreatment of the present invention and that uses cytotoxic and/or cytostatic agents against cancer cells or cells that are associated with or support cancer cells. In a preferred embodiment, the chemotherapeutic agent is an agent selected from the group consisting of an anti-metabolite, a microtubule inhibitor, a DNA damaging agent, an antibiotic, an anti—angiogenesis agent, a vascular disrupting agent, a molecularly targeted agent, and ations thereof.
As used herein, an "anti—metabolite" is a substance that reduces or inhibits a cell’s use of a chemical that is part of normal metabolism. Non-limiting examples of anti—metabolite agents or analogs thereof according to the present invention include antifolates, purine inhibitors, pyrimidine inhibitors, and combinations thereof.
As used herein, an "antifolate" is a substance that , s, or inhibits the use of folic acid (vitamin 89) by cells. Non—limiting examples of antifolates include methotrexate (DuraMed ceuticals, Inc.), pemetrexed (Eli Lilly), pralatrexate (Spectrum Pharmaceuticals), terin (Sigma Aldrich), pharmaceutically acceptable salts thereof, and combinations thereof.
As used herein, a "purine" is a compound that ns a fused six— membered and a five-membered nitrogen-containing ring. Non-limiting examples of purines that are important for ar metabolism e adenine, guanine, hypoxanthine, and xanthine. A "purine inhibitor" is a substance that alters, reduces or suppresses the production of a purine or the use of a purine by a cell. Non— ng examples of purine inhibitors e methotrexate (DuraMed ceuticals, Inc.), pemetrexed (Eli Lilly), hydroxyurea ol-Myers Squibb), 2— mercaptopurine (Sigma-Aldrich), 6-mercaptopurine (Sigma-Aldrich), fludarabine (Ben Venue Laboratories), clofarabine (Genzyme Corp.), nelarabine (GlaxoSmithKline), pralatrexate (Spectrum Pharmaceuticals), 6-thioguanine (Gate Pharmaceuticals), forodesine (BioCryst Pharmaceuticals), pentostatin (Bedford Laboratories), sapacitabine (Cyclacel Pharmaceuticals, Inc.), terin (Sigma Aldrich), azathioprine (GlaxoSmithKline), pharmaceutically acceptable salts thereof, and combinations thereof.
As used , a "pyrimidine" is a compound that contains a six- membered nitrogen-containing ring. Non—limiting examples of dines that are important for cellular metabolism e uracil, thymine, cytosine, and orotic acid. A "pyrimidine inhibitor" is a substance that alters, reduces, or suppresses the production of a pyrimidine or the use of a pyrimidine by the a cell. Non—limiting examples of pyrimidine inhibitors include 5-fluorouracil (Tocris Bioscience), tegafur (LGM Pharma), capecitabine (Xeloda) (Roche), cladribine (LGM Pharma), gemcitabine (Eli Lilly), cytarabine (Bedford Laboratories), bine (Eisai |nc.), floxuridine (Bedford tories), 5—azacytidine (Pharmion Pharmaceuticals), doxifluridine (Cayman Chemicals), thiarabine (Access Pharmaceuticals), itabine (SGX Pharmaceuticals), rexed (AstraZeneca), carmofur (Santa Cruz Biotechnology, Inc.), 6—azauracil (MP Biomedicals, LLC), ceutically acceptable salts thereof, and combinations thereof.
In a preferred aspect of the present invention, the anti-metabolite agent is selected from the group consisting of rouracil (Tocris Bioscience), tegafur (LGM Pharma), capecitabine a) (Roche), cladribine (LGM Pharma), rexate (DuraMed Pharmaceuticals, Inc.), pemetrexed (Eli Lilly), yurea (Bristol-Myers Squibb), 2—mercaptopurine (Sigma-Aldrich), 6-mercaptopurine (Sigma-Aldrich), fludarabine (Ben Venue Laboratories), gemcitabine (Eli Lilly), clofarabine (Genzyme Corp.), cytarabine (Bedford Laboratories), decitabine (Eisai |nc.), floxuridine (Bedford Laboratories), nelarabine (GlaxoSmithKline), pralatrexate (Spectrum Pharmaceuticals), 6—thioguanine (Gate Pharmaceuticals), 5—azacytidine ion Pharmaceuticals), doxifluridine (Cayman Chemicals), forodesine yst Pharmaceuticals), pentostatin (Bedford Laboratories), sapacitabine (Cyclacel Pharmaceuticals, Inc.), thiarabine (Access Pharmaceuticals), troxacitabine (SGX Pharmaceuticals), raltitrexed (AstraZeneca), aminopterin (Sigma Aldrich), carmofur (Santa Cruz Biotechnology, Inc.), azathioprine (GlaxoSmithKline), 6- azauracil (MP Biomedicals, LLC), pharmaceutically acceptable salts thereof, and combinations thereof.
As used herein, a "microtubule inhibitor" is a substance that disrupts the functioning of a ubule, such as the rization or the depolymerization of individual microtubule units. In one aspect of the present invention, the microtubule inhibitor may be selected from the group consisting of a microtubule- destabilizing agent, a microtubule—stabilizing agent, and ations thereof. A microtubule tor of the present invention may also be ed from the group consisting of a taxane, a vinca alkaloid, an epothilone, and combinations thereof. miting examples of microtubule inhibitors according to the present invention include BT-062 (Biotest), HMN-214 (D. Western eutics), eribulin mesylate (Eisai), vindesine (Eli Lilly), EC-1069 (Endocyte), EC-1456 (Endocyte), EC-531 (Endocyte), vintafolide (Endocyte), 2—methoxyestradiol (EntreMed), GTX—23O (GTX), trastuzumab emtansine (Hoffmann-La , crolibulin (Immune Pharmaceuticals), D1302A-maytansinoid conjugates (lmmunoGen), IMGN-529 oGen), lorvotuzumab mertansine (lmmunoGen), SAR-3419 (lmmunoGen), SAR-566658 (lmmunoGen), IMP-03138 (Impact Therapeutics), topotecan/vincristine combinations (LipoCure), BPH-8 (Molecular Discovery Systems), fosbretabulin tromethamine (OXiGENE), estramustine phosphate sodium (Pfizer), vincristine (Pierre Fabre), vinflunine (Pierre Fabre), vinorelbine (Pierre Fabre), 01 (Rexahn), cabazitaxel (Sanofi), STA—9584 (Synta Pharmaceuticals), stine, epothilone A, patupilone (Novartis), ixabepilone (Bristol-Myers Squibb), Epothilone D (Kosan Biosciences), paclitaxel (Bristol-Myers Squibb), xel (Sanofi-Aventis), HAI abraxane, DJ-927 (Daiichi Sankyo), discodermolide (CAS No: 127943—53-7), eleutherobin (CAS No.: 1745457), pharmaceutically acceptable salts thereof, and combinations thereof.
DNA damaging agents of the present invention include, but are not limited to, alkylating agents, platinum—based agents, alating agents, and inhibitors of DNA replication.
As used herein, an "alkylating agent" is a substance that adds one or more alkyl groups (CnHm, where n and m are integers) to a nucleic acid. In the present invention, an alkylating agent is selected from the group consisting of nitrogen mustards, nitrosoureas, alkyl sulfonates, triazines, ethylenimines, and combinations thereof. Non—limiting examples of nitrogen mustards include mechlorethamine (Lundbeck), mbucil (GlaxoSmithKline), cyclophosphamide (Mead Johnson 00.), bendamustine (Astellas), ifosfamide (Baxter International), melphalan (Ligand), melphalan flufenamide (Oncopeptides), and pharmaceutically acceptable salts thereof. Non-limiting es of nitrosoureas include streptozocin , carmustine (Eisai), lomustine (Sanofi), and ceutically acceptable salts f. miting examples of alkyl sulfonates include an (Jazz Pharmaceuticals) and pharmaceutically able salts f. Non-limiting examples of triazines include dacarbazine (Bayer), temozolomide (Cancer Research Technology), and pharmaceutically able salts thereof. Non-limiting examples of ethylenimines include thiotepa (Bedford Laboratories), altretamine (MGI Pharma), and pharmaceutically acceptable salts thereof. Other alkylating agents include ProLindac (Access), Ac-225 BC-8 (Actinium ceuticals), ALF-2111 (Alfact Innovation), trofosfamide (Baxter International), MDX—1203 (Bristol—Myers Squibb), thioureidobutyronitrile (CellCeutix), mitobronitol (Chinoin), mitolactol (Chinoin), nimustine (Daiichi ), glufosfamide on Pharmaceuticals), HuMax—TAC and PBD ADC combinations (Genmab), BP-C1 (Meabco), treosulfan (Medac), imox (Metronomx), improsulfan tosilate (Mitsubishi tanabe Pharma), ranimustine (Mitsubishi tanabe Pharma), ND-O1 (NanoCarrier), HH-1 (Nordic Nanovector), 22P1G cells and ifosfamide ations ex), estramustine phosphate (Pfizer), prednimustine (Pfizer), lurbinectedin (PharmaMar), trabectedin (PharmaMar), altreatamine (Sanofi), 33A le Genetics), fotemustine (Servier), nedaplatin (Shionogi), heptaplatin (Sk Holdings), uone rum Pharmaceuticals), SG—ZOOO (Spirogen), TLK—58747 (Telik), laromustine (Vion Pharmaceuticals), procarbazine (Alkem Laboratories Ltd.), and pharmaceutically acceptable salts thereof.
As used herein, a "platinum-based agent" is an anti-cancer substance that contains the metal platinum and analogs of such nces. The platinum may be in any oxidation state. um-based agents of the present invention include, but are not limited to, 1,2—diaminocyclohexane (DACH) derivatives, phenanthroimidazole Pt(ll) xes, platiunum IV compounds, bi- and tri-nuclear platinum compounds, demethylcantharidin-integrated platinum complexes, platinum— conjugated compounds, cisplatin nanoparticles and polymer micelles, sterically hindered platinum complexes, oxaliplatin (Debiopharm), satraplatin (Johnson Matthey), BBR3464 (Novuspharma ), ZDO473 (Astra Zeneca), cisplatin (Nippon Kayaku), JM-11 (Johnson Matthey), PAD (cis-dichlorobiscyclopentylamine platinum (||)), MBA ((trans—1,2—diaminocyclohexane) bisbromoacetato platinum (ll)), PHM ((1,2—Cyclohexanediamine) malonato platinum (||)), SHP ((1,2- Cyclohexanediamine) sulphato platinum (l|)), neo-PHM ((trans—R,R—1,2— Cyclohexanediamine) malonato platinum (||)), neo-SHP ((trans—R,R-1,2— Cyclohexanediamine)sulphato platinum (ll)), JM-82(Johnson Matthey), PYP ((1,2- Cyclohexanediamine) bispyruvato platinum (||)), PHIC ((1,2—Cyclohexanediamine) isocitrato platinum (||)), TRK—710 ((trans-R,R—1,2—cyclohexanediamine) [3-AcetyI methyl-2,4(3H,5H)—furandionato] platinum (||)), BOP ((1,2-Cyclooctanediamine) bisbromoacetato platinum (||)), JM—4O (Johnson Matthey), atin (UnionPharma), zeniplatin (LGM Pharma), Cl-973 (Parke-Davis), lobaplatin (Zentaris AG/Hainan Tianwang International Pharmaceutical), cycloplatam (LGM Pharma), WA2114R (miboplatin/lobaplatin) (Chembest Research Laboratories, Ltd.), latin (SKI2053R) (SK Chemicals), TNO—6 (spiroplatin) (Haihang Industry Co., Ltd.), ormaplatin platin) (LGM Pharma), JM-9 (iproplatin) (Johnson Matthey), BBR361O (Novuspharma S.p.A.), BBR3005 (Novuspharma S.p.A.), BBR3571 (Novuspharma S.p.A.), BBR3537 (Novuspharma S.p.A.), aroplatin (L-NDDP) (BOC Sciences), Pt-ACRAMTU en) Cl(ACRAMTU-S)](N03)2 (en=ethane-1,2— diamine, ACRAMTU=1- [2—(acridinylamino)ethyl]-1,3-dimethylthiourea)}), cisplatin- loaded |iposomes (LiPlasomes), SPl—O77 (Alza), lipoplatin (Regulon), l (Regulon), carboplatin (Johnson Matthey), nedaplatin (Shionogi Seiyaku), atin hydrate (Dainippon Sumitomo Pharma), ormaplatin (LGM Pharma), enloplatin (Lederle Laboratories), Cl973 -Davis), PEGylated tin, PEGylated carboplatin, PEGylated latin, transplatin (trans-diamminedichloroplatinum(lI); mixedZ:trans-[PtCl2{Z-HN=C(OMe)Me}(NH3)]), CD-37 (estradioI-platinum(ll) hybrid molecule), picoplatin rd Pharmaceuticals), H3N‘ ICI H300 H H3N\ CI ,Cl CI’Pt‘ >—_N\ ,CI CSN’— H C Pt CH3 Cl’PtIEIN CI’ \NH3 3 CI’ ‘N— 9 \ 7 H OCH3 9 O a WO 23574 PCT/U82016/015829 AH44 (Komeda et al., 2006; Harris et al., 2005; Qu et al., 2004), triplatinNC (Harris et al., 2005; Qu et al., 2004), ProLindac (Access), pharmaceutically acceptable salts thereof, and combinations thereof.
As used herein, an "intercalating agent" includes, but is not limited to, doxorubicin (Adriamycin), daunorubioin, idarubicin, ntrone, pharmaceutically acceptable salts thereof, prodrugs, and combinations thereof.
Non—limiting examples of inhibitors of DNA ation include, but are not limited to omerase inhibitors. As used herein, a "topoisomerase inhibitor" is a substance that decreases the expression or the activity of a topoisomerase. The topoisomerase tors according to the present invention may inhibit topoisomerase I, topoisomerase II, or both topoisomerase I and omerase II.
Non-limiting examples of topoisomerase I tors according to the present invention include irinotecan (Alchemia), APH-0804 (Aphios), camptothecin (Aphios), can merik), topotecan SmithKline), belotecan hydrochloride (Chon Kun Dang), firtecan pegol (Enzon), HN-30181A (Hanmi), hRS7—SN-38 (lmmunomedics), labetuzumab-SN-38 (lmmunomedics), etirinotecan pegol (Nektar Therapeutics), NK—012 (Nippon Kayaku), 3 (Serina Therapeutics), simmitecan hydrochloride prodrug (Shanghai HaiHe Pharmaceuticals), gimatecan (Sigma-Tau), namitecan (Sigma—Tau), SN-38 (Supratek ), TLC-388 hydrochloride (Taiwan Liposome Company), lamellarin D (PharmaMar), pharmaceutically acceptable salts thereof, and combinations thereof. Non-limiting examples of inhibitors of topoisomerase type II according to the present invention include Adva-27a (Advanomics), zoptarelin doxorubicin (Aeterna Zentaris), valrubicin (Anthra Pharmaceuticals), ne (AstraZeneca), doxorubicin (Avena Therapeutics), amsacrine (Bristol-Myers Squibb), etoposide phosphate (Bristol- Myers Squibb), etoposide (Novartis), oxane (Cancer Research Technology), cytarabine/daunorubicin combination (Celator ceuticals), CAP7.1 (CellAct Pharma), aldoxorubicin (Cthx), amrubicin hydrochloride (Dainippon Sumitomo Pharma), vosaroxin (Dainippon Sumitomo Pharma), daunorubicin (Gilead Sciences), milatuzumab/doxorubicin combination (lmmunomedics), aclarubicin (Kyowa Hakko Kirin), mitoxantrone (Meda), pirarubicin (Meiji), epirubicin (Pfizer), teniposide (Novartis), F—14512 e Fabre), elliptinium acetate (Sanofi), zorubicin (Sanofi), dexrazoxane (TopoTarget), sobuzoxane (Zenyaku , idarubicin (Pfizer), HU- 331 (Cayman Chemical), aurintricarboxylic acid (Sigma h), ceutically acceptable salts thereof, and combinations thereof.
Chemotherapeutic otics according to the t invention include, but are not limited to, actinomycin, cyclines, valrubicin, epirubicin, bleomycin, plicamycin, mitomycin, pharmaceutically acceptable salts thereof, prodrugs, and combinations thereof.
As used herein, the term "anti—angiogenesis agent" means any compound that prevents or delays nascent blood vessel formation from ng vessels. In the present invention, examples of anti-angiogenesis agents include, but are not limited to, pegaptanib, ranibizumab, bevacizumab (avastin), carboxyamidotriazole, TNP—470, CM101, lFN-d, lL-12, platelet factor 4, suramin, SU5416, thrombospondin, VEGFR nists, angiostatic steroids and heparin, cartilage-derived angiogenesis inhibitory factor, matrix metalloproteinase inhibitors, angiostatin, endostatin, 2—methoxyestradiol, tecogalan, tin, orvBS inhibitors, linomide, VEGF-Trap, terols, cortisone, tyrosine kinase inhibitors, anti- angiogenic siRNA, inhibitors of the complement system, vascular disrupting agents, and combinations thereof. Preferably, the anti-angiogenesis agent is bevacizumab.
VEGFR antagonists of the present invention include, but are not limited to, pazopanib, regorafenib, lenvatinib, sorafenib, sunitinib, ib, vandetanib, ntinib, nib, semaxanib, ZD6474, SU6668, AG-O13736, AZD2171, AEE788, MF1/MC-18F1, lMC-1C11, ramucirumab, and motesanib. VEGFR antagonists may also include, VEGF inhibitors such as bevacizumab, aflibercept, 2C3, r84, VEGF-Trap, and ranibizumab.
Angiostatic steroids of the t invention include any steroid that inhibits, attenuates, prevents angiogenesis or neovascularization, or causes regression of pathological vascularization. tatic steroids of the present invention include those disclosed in European Patent Application Serial No.
EP1236471 A2, as well as those stituted steroids sed in US. Patent Serial No. 4,599,331, those 21-hydroxy steroids disclosed in US. Patent Serial No. 4,771,042, those C11-functionalized steroids disclosed in International Application Serial No. diene-3,20-dione 21 -acetate, 6d—fluoro-170i,21-dihydroxy-16B—methylpregna-4,9(1 1)— diene-3,20-dione, 6d-fluoro-17d,21-dihydroxymethylpregna-4,9(11)-diene-3,20- dione 21-phosphonooxy and pharmaceutically acceptable salts thereof, hydrocortisone, tetrahydrocortisol, 17d-hydroxy- progesterone, 1 1o- epihydrocortisone, cortexolone, corticosterone, desoxycorticosterone, dexamethasone, cortisone 21-acetate, hydrocortisone 21-phosphate, 17d-hydroxy- 6d-methylpregnene-3,20-dione tate, oro-17or,21-dihydroxy-16or- methylpregna—4,9(11)-diene-3,20-dione, and A9(11)—etianic esters, all disclosed in International Application Serial No.
Cartilage-derived angiogenesis inhibitor factors include, but are not limited to, peptide in and chondromodulin |.
Matrix metalloproteinase inhibitors of the present invention include, but are not limited to, succinyl amates such as marimastat and SC903, sulphonamide hydroxamates such as 23A, phosphinamide hydroxamates, carboxylate inhibitors such as BAY12—9566, thiol inhibitors such as Compound B, aminomethyl benzimidazole analogues, peptides such as regasepin, and yclines such as minocycline. deB tors include, but are not limited to, ISZOI, P11 peptide, EMD 85189, and 66203, RGD peptide, RGD mimetics such as 8 36578-2, echistatin, antibodies or antibody fragments against deB in such as Vitaxin, which targets the extracellular domain of the dimer, cilengitide, and peptidomimetics such as 8247.
Anti—angiogenic siRNAs include, but are not d to, siRNAs targeting mRNAs that are upregulated during angiogenesis, optionally PEGylated siRNAs targeting VEGF or VEGFR mRNAs, and siRNAs targeting UPR (unfolded protein response)-|RE1d, XBP-1, and ATF6 mRNAs. Additionally, it has been shown that siRNAs that are, at minimum, 21 nucleotides in length, regardless of targeting sequence, suppress neovascularization (Kleinman, et al., 2008) and may be included in the anti—angiogenic siRNAs of the present invention.
Inhibitors of the complement system include, but are not limited to, ed native complement components such as soluble complement or type 1, soluble complement receptor type 1 g long homologous repeat-A, soluble ment Receptor Type 1—Sialyl Lewisx, complement or type 2, soluble decay accelerating factor, soluble membrane cofactor protein, soluble CD59, decay accelerating factor-CD59 hybrid, membrane cofactor protein-decay accelerating factor hybrid, C1 inhibitor, and C1q receptor, complement-inhibitory antibodies such as anti—C5 monoclonal antibody and anti—C5 single chain Fv, synthetic inhibitors of complement activation such as antagonistic peptides and analogs targeting C5a receptor, and lly occurring compounds that block complement activation such as heparin and related glycosaminoglycan compounds. onal inhibitors of the complement system are disclosed by Makrides des, 1998).
As used herein, the term "vascular ting agent" means any compound that targets existing vasculature, e.g. tumor vasculature, damages or destroys said vasculature, and/or causes central tumor necrosis. In the present invention, examples of vascular disrupting agents include, but are not limited to, ABT—751 (Abbott), 2 (Aventis), BCN105 mics), BMXAA (Antisoma), CAP (OxiGene), CAP (OxiGene), CYT997 (Cytopia), MPG-6827 (Myriad Pharmaceuticals), MN—O29 (MediciNova), NPl—2358 (Nereus), Oxi4503 (Oxigene), TZT-1027 (Daichi Pharmaceuticals), ZD6126 (AstraZeneca and Angiogene), pharmaceutically acceptable salts thereof, and combinations thereof.
As used herein, a "molecularly targeted agent" is a substance that eres with the function of a single molecule or group of molecules, ably those that are involved in tumor growth and ssion, when administered to a subject. Non-limiting examples of molecularly targeted agents of the present invention include signal transduction inhibitors, modulators of gene expression and other cellular functions, immune system modulators, antibody-drug conjugates (ADCs), and combinations thereof.
As used herein, a "signal transduction inhibitor" is a substance that disrupts ication between cells, such as when an extracellular signaling molecule activates a cell surface or. Non-limiting examples of signal transduction inhibitors of the t invention include anaplastic lymphoma kinase (ALK) tors, B-Raf inhibitors, epidermal growth factor inhibitors (EGFRi), ERK inhibitors, Janus kinase tors, MEK inhibitors, mammalian target of rapamycin (mTor) inhibitors, phosphoinositide 3—kinase inhibitors (PI3Ki), and Ras inhibitors.
As used herein, an "anaplastic lymphoma kinase (ALK) inhibitor" is a substance that (i) directly interacts with ALK, e.g., by binding to ALK and (ii) decreases the expression or the activity of ALK. Non—limiting examples of anaplastic lymphoma kinase (ALK) inhibitors of the present invention include crizotinib (Pfizer, New York, NY), CH5424802 i Pharmaceutical Co., Tokyo, Japan), GSK1838705 (GlaxoSmithKline, United Kingdom), Chugai 13d (Chugai Pharmaceutical Co., Tokyo, Japan), CEP28122 (Teva Pharmaceutical Industries, Ltd., Israel), 3 (Ariad Pharmaceuticals, Cambridge, MA), Cephalon 30 (Teva Pharmaceutical Industries, Ltd., Israel), X—396 (Xcovery, Inc., West Palm Beach, FL), Amgen 36 (Amgen Pharmaceuticals, Thousand Oaks, CA), ASP3026 (Astellas Pharma US, Inc., Northbrook, Illinois), and Amgen 49 (Amgen Pharmaceuticals, Thousand Oaks, CA), pharmaceutically acceptable salts thereof, and combinations thereof.
As used herein, a "B-Raf inhibitor" of the t invention is a substance that (i) directly interacts with B-Raf, e.g., by binding to B-Raf and (ii) decreases the sion or the activity of B-Raf. B-Raf inhibitors may be classified into two types by their respective binding modes. As used herein, "Type 1" B-Raf inhibitors are those inhibitors that target the ATP binding sites of the kinase in its active conformation. "Type 2" B—Raf tors are those inhibitors that preferentially bind to an ve conformation of the . miting examples of Type ‘I B- Raf inhibitors of the present invention include: WO 23574 PCT/U82016/015829 O \ O HNJEN l 1: Compound 7 / (Li et a/., 2010), KIN/w Compound 9 l (Id), Compound 10 Compound 13 0 (Id), Compound 14 (Id), dabrafenib (GlaxoSmithKline), GDC-O879 (Genentech), L-779450 B-Raf ), PLX3202 (Plexxikon), PLX4720 (Plexxikon), SB—590885 (GlaxoSmithKIine), SB—699393 (GlaxoSmithKline), vemurafenib (Plexxikon), ceutically acceptable salts thereof, and combinations thereof. Preferably, the type 1 RAF inhibitor is dabrafenib or a pharmaceutically acceptable salt thereof.
Non-limiting examples of Type 2 B-Raf inhibitors of the present ion include: N_ As used herein, an "EGFR inhibitor" is a substance that (i) directly interacts with EGFR, e.g. by binding to EGFR and (ii) ses the expression or the activity of EGFR. Non-limiting es of EGFR inhibitors according to the present invention include (+)—Aerop|ysinin-1 (CAS # 28656—91-9), 3-(4- lsopropylbenzylidenyl)—indo|in—2—one, ABT—806 (Life Science ceuticals), AC- 480 (Bristol-Myers Squibb), afatinib (Boehringer Ingelheim), AG 1478 (CAS # 153436—53—4), AG 494 (CAS # 133550—35—3), AG 555 (CAS # 133550—34—2), AG 556 (CAS # 1335501), AG 825 (CAS # 1490922), AG-490 (CAS # 134036-52—5), antroquinonol (Golden Biotechnology), AP—26113 (Ariad), ARRY334543 (CAS # 8452721), AST 1306 (CAS # -62—9), AVL-301 (Celgene), AZD8931 (CAS # 848942—61—0), BIBU 1361 (CAS # —84—8), BIBX 1382 (CAS # 196612—93—8), EMS-690514 (Bristol-Myers Squibb), BPlQ-l (CAS # 1747099), Canertinib (Pfizer), cetuximab (Actavis), cipatinib (Jiangsu Hengrui Medicine), CL—387,785 (Santa Cruz Biotech), compound 56 (CAS # 1717454), CTX-O23 (CytomX Therapeutics), CUDC-101 (Curis), dacomitinib (Pfizer), DAPH (CAS # 1459158), daphnetin (Santa Cruz Biotech), dovitinib lactate (Novartis), EGFR Inhibitor (CAS # 8791278), epitinib (Hutchison China MediTech), erbstatin Analog (CAS # 63177— 57-1), erlotinib (Astellas), gefitinib (AstraZeneca), GT-MAB 5.2—GEX (Glycotope), GW 583340 (CAS # 3880823), GW2974 (CAS # 202272—68—2), HDS 029 (CAS # 8810010), Hypericin (Santa Cruz Biotech), icotinib hydrochloride (Betapharma), JNJ-26483327 (Johnson & n), JNJ-28871063 (Johnson & Johnson), KD-O20 (Kadmon Pharmaceuticals), Iapatinib ditosylate SmithKline), Lavendustin A (Sigma), ustin C (Sigma), LY-3016859 (Eli Lilly), 945A (Hoffmann-La Roche), MM-151 (Merrimack), MT—O62 (Medisyn Technologies), necitumumab (Eli Lilly), neratinib r), zumab (Center of Molecular Immunology), NT-004 (NewGen eutics), mumab (Amgen), PD 153035 (CAS # 153436—54-5), PD 161570 (CAS # 1927059), PD 168393, PD 174265 (CAS # 2161630), pirotinib (Sihuan Pharmaceutical), poziotinib ), PP 3 (CAS # 5334—30—5), PR- 610 ta), nib (Jiangsu Hengrui Medicine), RG-13022 (CAS # 136831 6), rindopepimut (Celldex eutics), RPl—1 (CAS # —03—2), S-222611 (Shionogi), TAK 285 (CAS # 8710267), TAS-2913 (Taiho), theliatinib (Hutchison China MediTech), Tyrphostin 47 (RG—50864, AG—213) (CAS # 118409—60—2), Tyrphostin 51 (CAS # 1225205), Tyrphostin AG 1478 (CAS # 1751782), Tyrphostin AG 183 (CAS # 126433—07—6), Tyrphostin AG 528 (CAS # 133550—49—9), Tyrphostin AG 99 (CAS # 118409-59—9), Tyrphostin B42 (Santa Cruz Biotech), Tyrphostin B44 (Santa Cruz Biotech), Tyrphostin RG 14620 (CAS # 136831—49—7), vandetanib (AstraZeneca), varlitinib (Array BioPharma), vatalanib (Novartis), WZ 3146 (CAS # 1214265—56—1), WZ 4002 (CAS # 1213269—23—8), WZ8040 (CAS # 12142652), XL-647 (Exelixis), Z—650 (HEC , ZM 323881 (CAS # - -7), pharmaceutically acceptable salts thereof, and combinations thereof.
Preferably, the EGFR inhibitor is selected from the group consisting of panitumumab, erlotinib, pharmaceutically acceptable salts thereof, and combinations thereof.
As noted above, the solid forms of the present invention are ERK inhibitors. As used herein, an "ERK inhibitor" is a substance that (i) directly interacts with ERK, including ERK1 and ERK2, e.g., by binding to ERK and (ii) decreases the expression or the activity of an ERK protein kinase. Therefore, inhibitors that act upstream of ERK, such as MEK tors and RAF inhibitors, are not ERK inhibitors according to the present invention. The solid forms of the present invention may be administered as a combination therapy together with other ERK inhibitors, which e, for example, AEZS-131 (Aeterna Zentaris), AEZS-136 (Aeterna Zentaris), SCH—722984 (Merck & Co.), SCH-772984 (Merck & C0,), SCH—900353 53) (Merck & Co.), pharmaceutically acceptable salts thereof, and combinations thereof.
As used herein, a "Janus kinase inhibitor" is a substance that (i) directly interacts with a Janus kinase, e.g., by binding to a Janus kinase and (ii) decreases the expression or the activity of a Janus kinase. Janus kinases of the present invention include Tyk2, Jak1, Jak2, and Jak3. Non-limiting examples of Janus kinase tors of the present invention include ruxolitinib (lncyte Corporation, Wilmington, DE), baricitinib (lncyte ation, Wilmington, DE), tofacitinib (Pfizer, New York, NY), VX—509 (Vertex Pharmaceuticals, Inc., Boston, MA), GLPGO634 (Galapagos NV, Belgium), CEP-33779 (Teva Pharmaceuticals, Israel), ceutically acceptable salts thereof, and ations thereof As used herein, a "MEK inhibitor" is a substance that (i) directly interacts with MEK, e.g., by binding to MEK and (ii) decreases the expression or the activity of MEK. Therefore, inhibitors that act upstream of MEK, such as RAS inhibitors and RAF inhibitors, are not MEK inhibitors according to the present invention. MEK inhibitors may be fied into two types depending on whether the inhibitor competes with ATP. As used herein, a "Type 1" MEK tor is an inhibitor that competes with ATP for binding to MEK. A "Type 2" MEK inhibitor is an inhibitor that does not compete with ATP for binding to MEK. Non-limiting examples of type 1 MEK tors according to the present invention include bentamapimod (Merck KGaA), L783277 (Merck), R009221O (Roche), pharmaceutically acceptable salts thereof, and combinations thereof. Preferably, the type 1 MEK inhibitor is 1O (Roche) or a pharmaceutically acceptable salt thereof. Non-limiting es of type 2 MEK tors according to the present invention include anthrax toxin, lethal factor portion of anthrax toxin, ARRY-142886 (6-(4-bromo-2—chloro-phenylamino)—7- fluoromethyl—3H—benzoimidazoIe—5-carboxylic acid (2—hydroxy-ethoxy)—amide) (Array rma), ARRY—438162 (Array BioPharma), AS-1940477 (Astellas), MEK‘I62 (Array BioPharma), PD 098059 —amino—3'-methoxyphenyl)— oxanaphthalenone), PD 184352 (Cl—1040), PD-0325901 (Pfizer), pimasertib (Santhera Pharmaceuticals), refametinib (AstraZeneca), selumetinib (AZD6244) (AstraZeneca), TAK-733 (Takeda), trametinib (Japan Tobacco), UO126 (1 ,4-diamino- 2,3—dicyano—1,4—bis(2—aminophenylthio)butadiene) (Sigma), RDEA119 (Ardea Biosciences/Bayer), pharmaceutically acceptable salts thereof, and combinations thereof. Preferably, the type 2 MEK inhibitor is trametinib or a pharmaceutically able salt thereof. Other MEK inhibitors include, without limitation, antroquinonol (Golden Biotechnology), AS—1940477 (Astellas), 988 (Merck KGaA), Bl-847325 (Boehringer eim), E-6201 (Eisai), GDC-0623 (Hoffmann-La Roche), GDC—0973, RG422, RO4987655, RO5126766, SL327, WX—554 (Wilex), YopJ polypeptide, pharmaceutically acceptable salts thereof, and combinations thereof.
As used herein, an "mTOR tor" is a substance that (i) directly interacts with mTOR, e.g. by binding to mTOR and (ii) decreases the expression or the activity of mTOR. Non-limiting examples of mTOR tors according to the present invention include zotarolimus (Abeie), umirolimus (Biosensors), temsirolimus (Pfizer), sirolimus (Pfizer), mus NanoCrystaI (Elan Pharmaceutical Technologies), sirolimus TransDerm (TransDerm), sirolimus-PNP (Samyang), imus (Novartis), biolimus A9 (Biosensors), rolimus ), rapamycin, TOD-10023 (Terumo), DE-109 (MacuSight), 1 (MacuSight), MS-R002 (MacuSight), MS—R003 (MacuSight), Perceiva ight), XL—765 (Exelixis), quinacrine (Cleveland BioLabs), PKl-587 (Pfizer), PF-O4691502 (Pfizer), GDC—098O (Genentech and Piramed), dactolisib (Novartis), CC-223 (Celgene), PWT-33597 (Pathway Therapeutics), P-717O (Piramal Life Sciences), LY—3023414 (Eli Lilly), INK- 128 (Takeda), CDC—0084 (Genentech), DS-7423 (Daiichi Sankyo), DS-3078 (Daiichi Sankyo), CC-115 (Celgene), CBLC-137 land BioLabs), AZD—2014 (AstraZeneca), X-48O (Xcovery), X-414 (Xcovery), EC-0371 (Endocyte), VS—5584 tem), PQR-401 (Piqur), PQR-316 (Piqur), 1 (Piqur), PQR-309 (Piqur), PF—O6465603 (Pfizer), NV—128 (Novogen), nPT—MTOR (Biotica logy), BC—21O (Biotica Technology), WAY-600 (Biotica Technology), WYE-354 (Biotica Technology), WYE—687 (Biotica Technology), LOR—220 (Lorus eutics), HMPL— 518 (Hutchison China MediTech), GNE-317 (Genentech), EC-0565 (Endocyte), CC- 214 (Celgene), and ABTL—0812 (Ability Pharmaceuticals).
As used herein, a "Pl3K inhibitor" is a substance that decreases the expression or the ty of phosphatidylinositoI—3 kinases (PI3Ks) or downstream proteins, such as Akt. Pl3Ks, when activated, orylate the inositol ring 3'-OH group in ol phospholipids to generate the second messenger phosphatidylinosito|-3,4,5-trisphosphate (Pl-3,4,5-P(3)). Akt interacts with a phospholipid, causing it to translocate to the inner membrane, where it is phosphorylated and activated. Activated Akt modulates the function of numerous substrates involved in the regulation of cell survival, cell cycle progression and cellular growth.
Non-limiting es of P|3K inhibitors according to the present ion e A-674563 (CAS # 5523252), AGL 2263, AMG-319 (Amgen, Thousand Oaks, CA), AS-O41164 (5-benzo[1,3]dioxo|—5-ylmethylene—thiazolidine- 2,4-dione), AS—604850 (5—(2,2—Difluoro—benzo[1,3]dioxoly|methylene)—thiazolidine- 2,4-dione), AS—60524O (5-quinoxilin-6—methylene-1,3—thiazolidine-2,4-dione), AT7867 (CAS # 8575311 ), benzimidazole series, Genentech (Roche Holdings Inc., South San sco, CA), BML-257 (CAS # 323875), CAL-120 (Gilead Sciences, Foster City, CA), CAL—129 (Gilead Sciences), CAL—130 (Gilead Sciences), CAL—253 (Gilead Sciences), CAL-263 (Gilead Sciences), CAS # 612847-09—3, CAS # 681281- 88—9, CAS # 75747-14—7, CAS # 925681-41—0, CAS # 98510—80—6, CCT128930 (CAS # 885499-61—6), CH5132799 (CAS # 1007207—67-1), CHR-4432 (Chroma Therapeutics, Ltd., Abingdon, UK), FPA 124 (CAS # 902779—59—3), GS—1101 (CAL— 101) (Gilead es), GSK 690693 (CAS # 9371740), H-89 (CAS # 127243- 85—0), Honokiol, |C87114 (Gilead e), lPl—145 (Intellikine Inc), KAR—4139 (Karus Therapeutics, Chilworth, UK), KAR-4141 (Karus Therapeutics), KIN-1 (Karus eutics), KT 5720 (CAS # 108068—98—0), Miltefosine, MK—2206 dihydrochloride (CAS # 10323502), ML-9 (CAS # 1056371), Naltrindole Hydrochloride, OXY- 111A (NormOxys lnc., Brighton, MA), sine, PHT—427 (CAS # 1191951—57—1), Pl3 kinase delta inhibitor, Merck KGaA (Merck & Co., ouse Station, NJ), P|3 kinase delta inhibitors, Genentech (Roche gs Inc.), Pl3 kinase delta inhibitors, Incozen (Incozen Therapeutics, Pvt. Ltd., Hydrabad, India), Pl3 kinase delta inhibitors—2, Incozen (Incozen Therapeutics), PI3 kinase inhibitor, Roche-4 (Roche Holdings Inc), Pl3 kinase inhibitors, Roche (Roche Holdings Inc), Pl3 kinase inhibitors, Roche-5 (Roche Holdings Inc.), Pl3—alpha/delta inhibitors, Pathway Therapeutics ay Therapeutics Ltd., South San sco, CA), PIS-delta inhibitors, Cellzome (Cellzome AG, berg, Germany), Pl3—delta inhibitors, ikine (Intellikine |nc., La Jolla, CA), PIS-delta inhibitors, Pathway Therapeutics-1 (Pathway Therapeutics Ltd.), PIS—delta inhibitors, Pathway Therapeutics-2 (Pathway Therapeutics Ltd.), Pl3—delta/gamma inhibitors, Cellzome (Cellzome AG), PI3- gamma inhibitors, Cellzome ome AG), Pl3-delta/gamma tors, Intellikine (Intellikine lnc.), Pl3—delta/gamma inhibitors, Intellikine (Intellikine |nc.), PIS—delta/gamma inhibitors, Pathway Therapeutics (Pathway Therapeutics Ltd.), Pl3- WO 23574 PCT/U82016/015829 delta/gamma inhibitors, y Therapeutics (Pathway Therapeutics Ltd.), P|3- gamma inhibitor Evotec (Evotec), Pl3-gamma inhibitor, Cellzome (Cellzome AG), mma inhibitors, Pathway Therapeutics ay Therapeutics Ltd.), P|3K gamma inhibitors, Intellikine-1 (Intellikine |nc.), P|3K delta/gamma inhibitors, Intellikine—1 (Intellikine lnc.), pictilisib (GDC—0941) (Roche Holdings Inc.), PIK—90 (CAS # 6773384), SC-103980 r, New York, NY), SF-1126 (Semafore Pharmaceuticals, apolis, IN), SH—5, SH—6, Tetrahydro in, TG100—115 (Targegen Inc., San Diego, CA), Triciribine, X-339 ry, West Palm Beach, FL), XL499 (Evotech, Hamburg, Germany), pharmaceutically acceptable salts thereof, and combinations thereof. Preferably, the inhibitor of the Pl3K/Akt pathway is pictilisib (GDC—0941) or a pharmaceutically acceptable salt thereof.
As used herein, a "RAS inhibitor" is a substance that (i) directly interacts with RAS, e.g., by binding to RAS and (ii) decreases the expression or the activity of RAS. Non-limiting examples of RAS inhibitors according to the present invention include farnesyl transferase inhibitors (such as, e.g., tipifarnib and lonafarnib), farnesyl containing small molecules (such as, e.g., salirasib and TLN—4601), DCAI, as described by Maurer (Maurer, et al., 2012), Kobe0065 and Kobe2602, as described by Shima (Shima, et al., 2013), and HBS 3 (Patgiri, et al., 2011), and AlK—4 (Allinky), pharmaceutically acceptable salts thereof, and combinations thereof.
As used herein, "gene expression" is a process by which the information from DNA is used in the formation of a polypeptide. A "modulator of gene expression and other cellular functions" is a substance that affects gene expression and other works of a cell. miting examples of such modulators include hormones, e deacetylase inhibitors (HDACi), and cyclin-dependent kinase inhibitors (CDKi), and poly ADP ribose polymerase (PARP) inhibitors.
In the present invention, a "hormone" is a substance released by cells in one part of a body that s cells in another part of the body. Non-limiting examples of hormones according to the present invention include prostaglandins, leukotrienes, prostacyclin, thromboxane, amylin, antimullerian hormone, adiponectin, adrenocorticotropic hormone, ensinogen, angiotensin, vasopressin, atriopeptin, brain natriuretic peptide, calcitonin, cholecystokinin, corticotropin- releasing hormone, encephalin, endothelin, erythropoietin, follicle—stimulating hormone, galanin, gastrin, ghrelin, glucagon, gonadotropin-releasing e, growth hormone—releasing hormone, human chorionic gonadotropin, human placental lactogen, growth hormone, inhibin, insulin, somatomedin, leptin, liptropin, luteinizing hormone, melanocyte stimulating hormone, n, orexin, oxytocin, pancreatic polypeptide, parathyroid hormone, prolactin, prolactin releasing hormone, relaxin, renin, secretin, somatostain, thrombopoietin, thyroid—stimulating hormone, testosterone, dehydroepiandrosterone, androstenedione, dihydrotestosterone, erone, estradiol, e, estriol, cortisol, progesterone, calcitriol, and calcidiol.
Some compounds interfere with the activity of n hormones or stop the production of n hormones. Non—limiting examples of hormone-interfering compounds according to the present invention include tamoxifen (Nolvadex®), anastrozole (Arimidex®), letrozole (Femara®), and fulvestrant (Faslodex®). Such compounds are also within the meaning of hormone in the present invention.
As used herein, an "HDAC inhibitor" is a substance that (i) directly interacts with HDAC, e.g., by binding to HDAC and (ii) decreases the expression or the activity of HDAC. miting examples of HDAC tors according to the present ion include 480-201 (480 AG), 4SC—202 (Takeda), abexinostat (Celera), AN-1 (Titan ceuticals, Inc.), Apicidine (Merck & Co., Inc.), AR-42 (Arno Therapeutics), ARQ—7OORP (ArQule), Avugane (TopoTarget AS), azelaic hydroxamate-Q-anilide (AAHA), belinostat (TopoTarget), butyrate (Enzo Life Sciences, Inc.), CG—1255 (Errant Gene Therapeutics, LLC), 1 (Errant Gene Therapeutics, LLC), CG—200745 (CrystalGenomics, |nc.), chidamide (Shenzhen Chipscreen Biosciences), CHR—3996 (Chroma Therapeutics), ORA—024781 (Pharmacyclics), CS-3158 (Shenzhen Chipscreen Biosciences), CU-903 (Curis), DAC—60 (Genextra), entinostat (Bayer), hyaluronic acid c acid ester (HA—But), IKH-02 (lkerChem), IKH-35 (lkerChem), lTF-2357 (ltalfarmaco), lTF-A (ltalfarmaco), JNJ—16241199 (Johnson & Johnson), KA—001 (Karus Therapeutics), KAR—SOOO (Karus eutics), KD-515O (Kalypsys), KD-517O (Kalypsys), KLYP-278 sys), KLYP-298 (Kalypsys), KLYP-319 (Kalypsys), KLYP-722 (Kalypsys), m- carboxycinnamic acid droxamide (CBHA), MG-2856 lGene), MG-3290 (MethylGene), MG-4230 (MethylGene), MG—4915 (MethylGene), MG—5026 (MethylGene), MGCD-0103 (MethylGene |nc.), mocetinostat (MethylGene), MS 275 (Schering AG), NBM-HD-1 (NatureWise), NVP-LAQ824 (Novartis), OClD-4681— S-O1 (Orchid ceuticals), oxamflatin ((2E)[3—[(phenylsufonyl) aminol phenyl]-pent—2—enynohydroxamic acid), panobinostat (Novartis), PCl—34051 (Pharmacyclics), phenylbutyrate (Enzo Life Sciences, Inc.), pivaloyloxymethyl butyrate (AN-9, Titan Pharmaceuticals, Inc.), pivanex (Titan Pharmaceuticals, Inc.), pracinostat (SBIO), PX—117794 (TopoTarget AS), PXD-118490 0140) arget AS), pyroxamide (suberoylaminopyridineamide hydroxamic acid), resminostat (Takeda), RG-2833 (RepliGen), ricolinostat (Acetylon), romidepsin (Astellas), SB-1304 ), SB-1354 (S*B|O), SB-623 (Merrion Research | Limited), SB—624 on Research | Limited), SB—639 (Merrion Research | Limited), SB-939 (S*B|O), Scriptaid (N-Hydroxy-1,3-dioxo—1H-benz[de]isoquinoline-2(3H)- hexan , SK—7041 (ln2Gen/SK Chemical Co.), 8 n/SK Chemical Co.), suberoylanilide hydroxamic acid (SAHA), amide hydroxamic acid, tributyrin (Sigma Aldrich), trichostatin A (TSA) (Sigma Aldrich), valporic acid (VPA) (Sigma Aldrich), vorinostat (Zolinza), WF-2708ZB (Fujisawa Pharmaceutical Company, Ltd.), pharmaceutically acceptable salts thereof, and combinations thereof. Preferably, the HDAC inhibitor is romidepsin, pharmaceutically acceptable salts f, and combinations thereof.
As used herein, "CDK" is a family of protein s that regulate the cell cycle. Known CDKs include cdk1, cdk2, ckd3, ckd4, cdk5, cdk6, cdk7, cdk8, cdk9, cdk10, and cdk11. A "CDK inhibitor" is a substance that (i) directly interacts with CDK, e.g. by binding to CDK and (ii) ses the expression or the activity of CDK. Non-limiting examples of CDK inhibitors according to the present invention include 2—Hydroxybohemine, 3—ATA, 5-lodo—Indirubin-3'-monoxime, 9— Cyanopaullone, ne A, Alsterpaullone 2—Cyanoethyl, alvocidib (Sanofi), AM-5992 (Amgen), Aminopurvalanol A, Arcyriaflavin A, AT—7519 (Astex Pharmaceuticals), AZD 5438 (CAS # 6023066), EMS-265246 (CAS # 582315-72—8), BS-181 (CAS # 1092443—52-1), Butyrolactone | (CAS # 87414-49—1), Cdk/Crk Inhibitor (CAS # 7842112), Cdk1/5 Inhibitor (CAS # 90-8), Cdk2 Inhibitor II (CAS # —13-4), Cdk2 Inhibitor IV, NU6140 (CAS # 4447231), Cdk4 Inhibitor (CAS # 546102—60-7), Cdk4 Inhibitor ||| (CAS # 2653128), Cdk4/6 Inhibitor IV (CAS # 359886—84-3), Cdk9 Inhibitor II (CAS # 140651-18—9), CGP , CR8, CYC-065 (Cyclacel), dinaciclib (Ligand), (R)—DRFO53 dihydrochloride (CAS # 1056016—06—8), Fascaplysin, Flavopiridol, Hygrolidin, Indirubin, LEE-011 (Astex Pharmaceuticals), WO 23574 PCT/U82016/015829 LY—2835219 (Eli Lilly), milciclib e (Nerviano Medical Sciences), MM-D37K (Maxwell Biotech), N9-lsopropyl-olomoucine, NSC 625987 (CAS # 1419924), NU2058 (CAS # 161058-83—9), NU6102 (CAS # 4447226), Olomoucine, ON- 108600 (Onconova), ON-123300 (Onconova), Oxindole l, —O5 (Piramal), P- 276—00 (Piramal), iclib (Pfizer), PHA—767491 (CAS # 845714—00—3), PHA— 793887 (CAS # 7186302), PHA-848125 (CAS # 8025397), Purvalanol A, Purvalanol B, R547 (CAS # 741713—40—6), RO—3306 (CAS # 872573—93—8), Roscovitine, SB-1317 (SBIO), SCH 900776 (CAS # 8914946), SEL-12O (Selvita), seliciclib (Cyclacel), SNS—032 (CAS # 345627—80—7), SU9516 (CAS # 3770901), WHl-P18O (CAS # 211555-08—7), pharmaceutically acceptable salts thereof, and combinations thereof. Preferably, the CDK inhibitor is selected from the group consisting of dinaciclib, iclib, pharmaceutically acceptable salts thereof, and combinations thereof.
As used herein, a "poly ADP ribose rase (PARP) inhibitor" is a substance that decreases the expression or activity of poly ADP ribose polymerases (PARPs) or downstream proteins. Non-limiting examples of poly ADP ribose polymerase (PARP) inhibitors of the present invention include PF01367338 (Pfizer, New York, NY), olaparib (AstraZeneca, United Kingdom), iniparib i-Aventis, Paris, France), veliparib (Abbott Laboratories, Abbott Park, IL), MK 4827 (Merck, White House n, NJ), CEP 9722 (Teva Pharmaceuticals, ), LT-673 (Biomarin, San Rafael, CA), and BSI 401 (Sanofi-Aventis, Paris, France), ceutically acceptable salts thereof, and combinations thereof.
As used herein, "immunotherapeutic agent" means any anti-cancer agent that is ible with the solid forms of the present invention and that uses a substance that alters the immune response by augmenting or reducing the ability of the immune system to produce dies or sensitized cells that recognize and react with the antigen that initiated their production. Immunotherapeutic agents may be recombinant, synthetic, or l preparations and include cytokines, corticosteroids, cytotoxic agents, thymosin, and immunoglobulins. Some immunotherapeutic agents are naturally present in the body, and certain of these are available in pharmacologic preparations. Examples of immunotherapeutic agents include, but are not limited to, granulocyte colony—stimulating factor (G—CSF), erons, imiquimod and cellular membrane fractions from bacteria, lL-2, lL-7, IL- 12, CCL3, CCL26, CXCL7, and synthetic cytosine phosphate—guanosine (CpG).
In one preferred embodiment, the immunotherapeutic agent is an immune oint inhibitor. As used herein, an "immune checkpoint inhibitor" means a substance that blocks the activity of molecules involved in attenuating the immune response. Such molecules include, for example, cytotoxic T-lymphocyte- associated antigen 4 (CTLA—4) and programmed cell death protein 1 (PD-1).
Immune checkpoint tors of the present invention include, but are not limited to, umab (Bristol-Myers Squibb), tremelimumab (Pfizer), MDX-1106 ex, |nc.), MK3475 (Merck), CT-O11 (CureTech, Ltd.), AMP-224 (Amplmmune), MDX— 1105 (Medarex, |nc.), |MP321 (lmmutep SA), and MGA271 (Macrogenics).
In the t invention, the term "radionuclide" means a radioactive substance stered to the patient, e.g., enously or orally, after which it penetrates via the patient’s normal metabolism into the target organ or tissue, where it delivers local radiation for a short time. Examples of radionuclides include, but are not limited to, l-125, At—211, , Cu—67, l-131, Sm-153, Re-186, P—32, Re—188, ln—114m, and Y-90.
In the present invention, the term "photoactive therapeutic agent" means compounds and itions that become active upon exposure to light.
Certain examples of photoactive therapeutic agents are sed, e.g., in US.
Patent Application Serial No. 2011/0152230 A1, active Metal Nitrosyls For Blood Pressure Regulation And Cancer Therapy." In the present invention, the term "radiosensitizing agent" means a compound that makes tumor cells more sensitive to radiation therapy. Examples of radiosensitizing agents include misonidazole, idazole, zamine, and trans sodium crocetinate.
In the present invention, an tive amount" or a "therapeutically effective amount" of one or more of the solid forms of the present invention or another anti-cancer agent of the invention, including the ceutical compositions containing same, is an amount of such solid form or composition that is sufficient to effect beneficial or desired results as bed herein when administered to a subject. Effective dosage forms, modes of administration, and dosage amounts may be determined empirically, and making such determinations is within the skill of the art. It is understood by those skilled in the art that the dosage amount will vary with the route of administration, the rate of excretion, the duration of the treatment, the identity of any other drugs being administered, the age, size, and species of subject, e.g., human patient, and like factors well known in the arts of medicine and veterinary medicine. In general, a suitable dose of one or more of the solid forms of the present invention or a pharmaceutical composition according to the invention will be that amount of the solid form or pharmaceutical composition, which is the lowest dose effective to produce the desired effect. The effective dose of a solid form or ceutical composition of the present invention may be administered as two, three, four, five, six or more sub-doses, administered separately at riate intervals throughout the day.
A suitable, non—limiting example of a dosage of a solid form of the present invention or another anti-cancer agent disclosed herein is from about 1 mg/kg to about 2400 mg/kg per day, such as from about 1 mg/kg to about 1200 mg/kg per day, 75 mg/kg per day to about 300 mg/kg per day, including from about 1 mg/kg to about 100 mg/kg per day. Other representative dosages of such agents include about 1 mg/kg, 5 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, mg/kg, 40 mg/kg, 45 mg/kg, 50 mg/kg, 60 mg/kg, 70 mg/kg, 75 mg/kg, 80 mg/kg, 90 mg/kg, 100 mg/kg, 125 mg/kg, 150 mg/kg, 175 mg/kg, 200 mg/kg, 250 mg/kg, 300 mg/kg, 400 mg/kg, 500 mg/kg, 600 mg/kg, 700 mg/kg, 800 mg/kg, 900 mg/kg, 1000 mg/kg, 1100 mg/kg, 1200 mg/kg, 1300 mg/kg, 1400 mg/kg, 1500 mg/kg, 1600 mg/kg, 1700 mg/kg, 1800 mg/kg, 1900 mg/kg, 2000 mg/kg, 2100 mg/kg, 2200 mg/kg, and 2300 mg/kg per day. The effective dose of a solid form of the present invention or other anti—cancer agents disclosed herein may be stered as two, three, four, five, six or more sub-doses, administered tely at appropriate intervals throughout the day.
The solid form of the t invention or other anti-cancer agents or pharmaceutical compositions containing same of the present invention may be administered in any desired and effective manner: for oral ingestion, or as an ointment or drop for local administration to the eyes, or for parenteral or other administration in any appropriate manner such as intraperitoneal, aneous, topical, intradermal, inhalation, ulmonary, rectal, vaginal, sublingual, intramuscular, intravenous, intraarterial, intrathecal, or intralymphatic. r, the solid form of the present invention or other anti-cancer agents or pharmaceutical compositions containing same of the present invention may be administered in conjunction with other treatments. The solid form of the present invention or other anti-cancer agents or the pharmaceutical compositions of the present ion may be encapsulated or ise protected against gastric or other ions, if desired.
The pharmaceutical compositions of the ion may comprise one or more active ingredients, e.g., one or more solid forms of the present invention optionally in combination with other anti-cancer agents anti-cancer agents, in admixture with one or more pharmaceuticalIy—acceptable diluents or carriers and, optionally, one or more other compounds, drugs, ingredients and/or materials.
Regardless of the route of administration selected, the agents/compounds of the present invention are formulated into ceutically-acceptable dosage forms by conventional methods known to those of skill in the art. See, e.g., ton, The Science and Practice of Pharmacy (21st Edition, Lippincott Williams and Wilkins, Philadelphia, PA.). ceutically acceptable diluents or carriers are well known in the art (see, e.g., ton, The Science and Practice of Pharmacy (21st Edition, Lippincott Williams and Wilkins, Philadelphia, PA.) and The National Formulary (American Pharmaceutical Association, Washington, D.C.)) and include sugars (e.g., lactose, sucrose, mannitol, and ol), starches, cellulose preparations, calcium phosphates (e.g., dicalcium phosphate, tricalcium phosphate and m hydrogen phosphate), sodium e, water, aqueous solutions (e.g., saline, sodium chloride injection, Ringer's injection, se injection, dextrose and sodium chloride injection, lactated Ringer's injection), alcohols (e.g., ethyl alcohol, propyl alcohol, and benzyl alcohol), polyols (e.g., glycerol, propylene glycol, and polyethylene glycol), WO 23574 PCT/U82016/015829 organic esters (e.g., ethyl oleate and tryglycerides), biodegradable rs (e.g., polylactide-polyglycolide, poly(orthoesters), and poly(anhydrides)), elastomeric matrices, liposomes, microspheres, oils (e.g., corn, germ, olive, castor, sesame, cottonseed, and groundnut), cocoa butter, waxes (e.g., suppository waxes), paraffins, silicones, talc, silicylate, etc. Each ceutically acceptable t or carrier used in a pharmaceutical composition of the invention must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not ous to the subject. Diluents or rs suitable for a selected dosage form and ed route of administration are well known in the art, and acceptable diluents or carriers for a chosen dosage form and method of administration can be determined using ordinary skill in the art.
The pharmaceutical compositions of the invention may, optionally, contain additional ingredients and/or materials ly used in pharmaceutical compositions. These ingredients and materials are well known in the art and include (1) fillers or extenders, such as es, lactose, sucrose, glucose, mannitol, and silicic acid; (2) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, hydroxypropylmethyl cellulose, sucrose and acacia; (3) humectants, such as ol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, sodium starch glycolate, cross-linked sodium carboxymethyl cellulose and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption rators, such as quaternary ammonium compounds; (7) wetting agents, such as cetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such as talc, calcium stearate, magnesium te, solid polyethylene glycols, and sodium lauryl sulfate; (10) suspending agents, such as ethoxylated isostearyl WO 23574 PCT/U82016/015829 alcohols, polyoxyethylene sorbitol and sorbitan esters, rystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth; (11) buffering agents; (12) excipients, such as lactose, milk sugars, polyethylene glycols, animal and vegetable fats, oils, waxes, paraffins, cocoa , starches, tragacanth, ose derivatives, polyethylene glycol, silicones, bentonites, silicic acid, talc, salicylate, zinc oxide, aluminum hydroxide, calcium silicates, and polyamide powder; (13) inert diluents, such as water or other ts; (14) preservatives; (15) surface— active agents; (16) dispersing agents; (17) control-release or absorption-delaying agents, such as hydroxypropylmethyl ose, other polymer matrices, biodegradable polymers, liposomes, pheres, aluminum monostearate, gelatin, and waxes; (18) opacifying agents; (19) adjuvants; (20) wetting agents; (21) emulsifying and suspending agents; (22), solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene , 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, ydrofuryl l, polyethylene glycols and fatty acid esters of sorbitan; (23) propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane; (24) antioxidants; (25) agents which render the formulation ic with the blood of the intended recipient, such as sugars and sodium chloride; (26) thickening agents; (27) coating materials, such as lecithin; and (28) sweetening, flavoring, coloring, perfuming and preservative agents. Each such ingredient or material must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the subject. Ingredients and materials suitable for a selected dosage form and intended route of administration are well known in the art, and acceptable ingredients and materials for a chosen dosage form and method of administration may be determined using ordinary skill in the art.
The pharmaceutical compositions of the present ion suitable for oral administration may be in the form of capsules, cachets, pills, tablets, powders, granules, a solution or a suspension in an aqueous or non—aqueous liquid, an oil—in— water or water-in-oil liquid emulsion, an elixir or syrup, a pastille, a bolus, an electuary or a paste. These formulations may be prepared by methods known in the art, e.g., by means of conventional pan-coating, mixing, granulation or Iyophilization processes.
Solid dosage forms for oral administration les, tablets, pills, dragees, powders, es and the like) may be prepared, e.g., by mixing the active ingredient(s) with one or more pharmaceuticaIIy-acceptable diluents or carriers and, optionally, one or more fillers, ers, binders, humectants, disintegrating agents, solution retarding agents, absorption rators, wetting agents, absorbents, lubricants, and/or coloring agents. Solid compositions of a similar type may be employed as fillers in soft and hard-filled n capsules using a suitable excipient.
A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed s may be prepared using a suitable binder, lubricant, inert diluent, preservative, disintegrant, surface-active or dispersing agent.
Molded tablets may be made by molding in a suitable machine. The tablets, and other solid dosage forms, such as s, es, pills and es, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled e of the active ingredient therein. They may be sterilized by, for example, filtration through a bacteria-retaining filter. These compositions may also optionally contain opacifying agents and may be of a ition such that they release the active ingredient only, or preferentially, in a certain portion of the intestinal tract, optionally, in a delayed manner. The active ingredient can also be in microencapsulated form.
Liquid dosage forms for oral stration include pharmaceutically— acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
The liquid dosage forms may contain suitable inert diluents commonly used in the art. s inert diluents, the oral compositions may also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents. Suspensions may contain suspending agents.
The pharmaceutical compositions of the present invention for rectal or vaginal stration may be presented as a suppository, which may be prepared by mixing one or more active ingredient(s) with one or more suitable nonirritating diluents or carriers which are solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound. The pharmaceutical compositions of the present invention which are suitable for l stration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such pharmaceutically-acceptable diluents or carriers as are known in the art to be appropriate.
Dosage forms for the topical or transdermal administration e powders, sprays, ointments, pastes, creams, lotions, gels, ons, s, drops and inhalants. The active agent(s)/compound(s), including the solid forms of the present invention, may be mixed under sterile conditions with a suitable pharmaceutically-acceptable diluent or carrier. The ointments, pastes, creams and gels may contain excipients. Powders and sprays may contain excipients and lants.
The pharmaceutical compositions of the present invention suitable for parenteral administrations may comprise one or more agent(s)/compound(s) in combination with one or more pharmaceutically—acceptable sterile isotonic aqueous or non-aqueous ons, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain suitable antioxidants, buffers, solutes which render the formulation isotonic with the blood of the intended recipient, or suspending or thickening agents. Proper fluidity can be maintained, for example, by the use of g materials, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. These pharmaceutical compositions may also contain suitable adjuvants, such as wetting agents, emulsifying agents and sing agents. It may also be ble to include isotonic agents. In addition, ged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption.
In some cases, in order to prolong the effect of a drug (e.g., pharmaceutical formulation), it is desirable to slow its absorption from aneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water lity.
The rate of tion of the active agent/drug, including the solid forms of the present invention, then s upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally-administered agent/drug may be accomplished by dissolving or suspending the active agent/drug in an oil vehicle. Injectable depot WO 23574 PCT/U82016/015829 forms may be made by forming microencapsule matrices of the active ingredient in biodegradable polymers. Depending on the ratio of the active ingredient to polymer, and the nature of the particular polymer employed, the rate of active ient release can be controlled. Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body . The injectable materials can be sterilized for example, by tion h a bacterial—retaining .
The formulations may be present in unit-dose or multi-dose sealed containers, for example, ampules and vials, and may be stored in a lyophilized condition requiring only the addition of the sterile liquid diluent or carrier, for example water for injection, immediately prior to use. Extemporaneous injection solutions and suspensions may be ed from sterile powders, granules and tablets of the type described above.
The following examples are provided to further illustrate the nds, compositions and methods of the present invention. These examples are illustrative only and are not intended to limit the scope of the invention in any EXAMPLES EXAMPLE 1 Experimental s X-ray Powder Diffraction (XRPD) Transmission mode XRPD patterns were collected using an incident beam of Cu radiation produced using a fine-focus source. An elliptically graded multilayer mirror was used to focus Cu Kd X-ray radiation through the specimen and onto the detector. Prior to the analysis, a silicon specimen (NIST SRM 640d) was analyzed to verify that the observed position of the Si 111 peak was consistent with the NIST-certified on. A specimen of the sample was sandwiched between 3- pm-thick films and analyzed in transmission geometry. A beam-stop, short antiscatter extension, and antiscatter knife edge were used to minimize the background generated by air. Soller slits for the incident and diffracted beams were used to minimize ning from axial divergence. Diffraction patterns were collected using a scanning on-sensitive detector located 240 mm from the specimen. red ation and particle static effects were not assessed.
Reflection mode XRPD patterns were ted using an incident beam of Cu Kd radiation produced using a fine—focus source and a nickel filter. The diffractometer was configured using the symmetric Bragg—Brentano geometry. Prior to the analysis, a silicon en (NIST SRM 640d) was analyzed to verify that the observed position of the Si 111 peak was consistent with the NIST-certified position.
A specimen of the sample was prepared as a thin, circular layer centered on a silicon zero-background substrate. Antiscatter slits (SS) were used to minimize the background generated by air. Soller slits for the incident and cted beams were used to minimize broadening from axial divergence. Diffraction patterns were collected using a scanning position-sensitive detector located 240 mm from the sample. Preferred orientation and particle static effects were not assessed.
Under most circumstances, peaks within the range of up to about 30° 29 were selected. The location of the peaks along the x—axis (° 26) were rounded to one significant figure after the decimal point. Peak on variabilities are given to within 102° 26 based upon recommendations outlined in the USP discussion of variability in X-ray powder diffraction. The accuracy and precision associated with any particular measurement was not ined. Moreover, third party ements on independently prepared samples on different instruments may lead to variability which is greater than i02° 26. Per USP guidelines, variable hydrates and solvates may display peak variances greater than 0.20 26 and therefore peak variances of 02° 29 are not able to these materials. For d—space listings, the wavelength used to calculate d-spacings was 1.5405929A, the Cu-Kd1 wavelength. Variability associated with d—spacing estimates was calculated from the USP recommendation, at each ing, and provided in the respective data tables.
Fourier Transform Infrared (FT—IR) spectroscopy FT-IR spectra were acquired using a Fourier transform infrared spectrophotometer equipped with a mid/far IR source, an ed range potassium bromide (KBr) beamsplitter, and a deuterated triglycine sulfate (DTGS) detector.
Wavelength verification was performed using NIST SRM 1921b (polystyrene). An attenuated total reflectance (ATR) ory with a germanium (Ge) crystal was used for data acquisition. 256 co—added scans were collected at a spectral resolution of 2 cm'1. A background data set was acquired with a clean Ge crystal. A Log 1/R (R = reflectance) spectrum was obtained by taking a ratio of these two data sets against each other. Peak picking was performed using an absolute old near the baseline and a sensitivity of 75.
Differential Scanning Calorimetm (DSC) DSC analysis was performed using a differential scanning meter.
Temperature calibration was performed using NIST-traceable indium metal. The sample was placed into an aluminum DSC pan, covered with a lid, and the weight was accurately recorded. A weighed aluminum TOHSMP pan configured as the sample pan was placed on the reference side of the cell. Reported temperatures are rounded to 1 degree unless specified otherwise.
Raman oscopy Raman spectroscopy was performed using a dispersive RamanRXN3 (Kaiser Optical Systems Inc., Ann Arbor, MI) for in—situ reaction monitoring. The RamanRXN3 system uses an excitation wavelength of 785 nm, with an external cavity—stabilized, diode laser. All spectra were acquired using a 1/4" immersion optics probe with approximately 103 mW of laser power at the tip of the probe. The spectra were collected using an exposure time of 5 up to 15 s and with 5 spectrum accumulations. Wavelength and laser wavelength calibration were performed using an internal neon standard, and diamond Raman shift standard, respectively. The intensity calibration was med using a Kaiser Raman calibration accessory (Kaiser Optical Systems Inc., Ann Arbor, MI).
EXAMPLE 2 Preparation of Crystaline Free Base 4-(5-Chloroisopropylaminopyridinyl)— 1H-pyrrolecarboxylic acid [1 -(3-chlorophenyl)hydroxyethyl]amide hloroisopropylaminopyridinyl)-1H-pyrrolecarboxylic acid [1-(3-chloropheny|)hydroxyethyl]amide free base was prepared according to the following synthesis scheme. 1.lso ro lamine Step1 N/ 55~75°C 71.77% yield C5HZCIF|N (HUI-1L 257.43 C5H1OC|IN2 ASYM-111606 296.54 ASYM-1 12060 (HO)ZB ""? 1 .Anhydrous sodium carbonate 2. Palladium acetate Step2 tni'k N302 yclohexylphosphonium uoroborate NI \ 75~85°C / 74.94% yield \ COOCH3 llN2 CI N 296- 54 H0 ‘ H BNO s ASYM—112060 13312313 5 021123395045 TS ASYM-111938 ASYM-112393 ANH ANH 1.Lithium hydroxide monohydrate Stet" \ NI \ 2.Diethy|amine NI / / 60~70°c \ \ l COOCH3 COOH 74.00 A) erlda . \ CI CI N NH C21HZZCIN304S Ts C13H14C|N302 447.94 279.72 ASYM—112393 ASYM-112394 Step4 0" NI 1.HOBT. H20 N \ o 2. EDCI | 3-D'EA \ \ COOH \ \ NV 0' Cl :' NH C8H1LCINO 15~25°c NH ‘ OH 7881 0A: yield C13H14CIN302 279.72 17152 ASYM-112394 ASYM-111888 CI CZ1H22CIZN4OZ 433.33 ASYM—1 11935 In Step 1, a clean and dry 200 L glass-lined reactor was evacuated to -0.08 MPa, and then filled with nitrogen to normal pressure three times. Anhydrous ethanol (49.90 kg) was charged into the 200 L glass-lined reactor. ASYM-111606 (Asymchem) (12.70 kg) and isopropylamine (29.00 kg) were added into the mixture in turn. The mixture was heated to 65-75°C for refluxing. The mixture reacted at 65- 75°C. After 20 h, the on was sampled and analyzed by HPLC every 4-6 h until the content of ASYM-111606 was 31%. The mixture was cooled to C and was concentrated at 345°C under reduced pressure (5-0.08 MPa) until 13-26 L WO 23574 PCT/U82016/015829 remained. The organic phase was washed with a sodium chloride solution and was stirred for 20-30 min and settled for 20-30 min before separation. The organic phase was concentrated at 530°C under reduced pressure (5-006 MPa) until 13—20 L remained. eum ether (8.55 kg) was added into the concentrated mixture. The mixture was transferred into a 20 L rotary evaporator and continued trating at 530°C under reduced pressure (5-0.06 MPa) until 13-20 L remained. Then petroleum ether (8.55 kg) was added into the concentrated e. The e was cooled to 0-5°C and stirred for crystallization. After 1h, the mixture was sampled and analyzed by wt% every 1—2 h until the wt% of the mother liquor was 511% or the change of the wt% n consecutive samples was 31%. The mixture was filtered with a 10 L filter flask. The filter cake was sampled and analyzed for purity by HPLC. 10.50 kg of product was recovered as a brownish yellow solid at 99.39% .
In Step 2, a clean and dry 300 L glass-lined reactor was evacuated to 3-0.08 MPa, and then filled with nitrogen to normal pressure three times. Glycol dimethyl ether (73.10 kg) was charged into the 300 L glass-lined reactor at 20—30°C.
ASYM-112060 (Asymchem) (10.46 kg) and ASYM-111938 (Asymchem) (12.34 kg, 11.64 kg after corrected) were added into the mixture in turn under the protection of nitrogen. Maintaining the temperature at 20-30°C, purified water (10.50 kg) and anhydrous sodium carbonate (5.67 kg) were added into the mixture. Palladium acetate (0.239 kg) and tricyclohexylphosphonium tetrafluoroborate (0.522 kg) were added into the mixture under the protection of nitrogen. After addition, the mixture was evacuated to 3-006 MPa, and then filled with nitrogen to normal re. This was repeated for ten times until residual oxygen was 5300 ppm. The mixture was heated to 75-85°C for refluxing. The mixture d at 75—85°C. After 4 h, the mixture was sampled and analyzed by HPLC every 2—3 h for content of ASYM- 112060. The content of ASYM—112060 was 6.18%, so additional ASYM-111938 (0.72 kg) was added and continued reaction until the content of ASYM-112060 was 53%. The mixture was cooled to 25-35°C and filtered with a 30 L stainless steel vacuum filter. The filter cake was soaked and washed twice with THF (14.10kg).
The filtrate and washing liquor were combined and concentrated at 350°C under reduced pressure (5-0.08 MPa) until 10-15 L remained. The mixture was cooled to —25°C. Methanol (11.05 kg) was added into the concentrated mixture. Then the mixture was stirred for crystallization. After 2 h, the mixture was sampled and analyzed by HPLC every 2—4 h until the wt% of the mother liquor was 52%. The mixture was ed with a 30 L stainless steel vacuum . The filter cake was soaked and washed twice with methanol (8.30 kg). The filter cake was transferred into a 50 L plastic drum. Then ethyl acetate (7.10 kg) and petroleum ether (46.30 kg) were added into the drum. The mixture was stirred for 1.5-2 h and then filtered with a nutsche filter. The filter cake was soaked and washed with petroleum ether (20.50 kg). The filter cake was dried in the e filter under nitrogen at 30-40°C. After 8 h, the solid was sampled and Karl Fischer (KF) is was performed in intervals of 4—8 h to monitor the drying s. Drying was completed when the KF result was 51.0% water. During drying, the solid was turned over and mixed every 4-6 h. 12.15 kg of product was recovered as a brownish yellow solid at 98.32% .
In Step 3, a clean and dry 300 L glass-lined reactor was evacuated to -0.08 MPa, and then filled with nitrogen to normal pressure three times. THF (62.58 kg) was charged into the 300 L glass—lined r at 15—30°C. Then the stirrer was started. ASYM-112393 (12.00 kg, 11.70 kg after corrected) was added into the mixture. The mixture was stirred until the solid dissolved completely.
Maintaining the temperature at C, a m hydroxide solution which was prepared with lithium hydroxide monohydrate (5.50 kg) in purified water (70.28 kg) was added into the mixture. Then diethylamine (3.86 kg) was added. The mixture was heated to (SO—70°C for refluxing. The mixture reacted at 60—70°C. After 30 h, the on was sampled and analyzed by HPLC every 4-6 h until the content of intermediate at relative retention time (RRT)=1.39—1.44 was <1% and the content of ASYM-112393 was <1 %. HPLC conditions for this analysis are set forth in Table 1.
Table 1: HPLC Parameters Column: ACE 3 C18, 4.6X150 mm, (ACE1546) Column 30°C Temperature: Flow rate 1.1mL/min Injection 10pL Volume: Mobile Phase A: 0.05% TFA in water (v/v) Mobile Phase B: 0.05% TFA in Acetonitrile (v/v) Gradient Table: T(min): B% 0.0 5 4.0 20 14.0 85 14.1 5 18.5 5 ion: UVat215nm e 18.5min The mixture was cooled to 25-35°C and MTBE (25.97 kg) was added into the mixture. The e was stirred for 20-30 min and filtered via an in-line fluid filter. The filtrate was transferred into a 300 L glass-lined reactor and settled for 20- min before separation. The pH of the obtained aqueous phase was adjusted with a 6 N hydrochloric acid solution which was prepared from trated hloric acid (14.86 kg) in purified water (10.88 kg) at the rate of 5-8 kg/h at 15-25°C until the pH was 1—2. The pH of the mixture was adjusted again with a saturated sodium carbonate solution which was prepared from sodium ate (5.03 kg) in purified water (23.56 kg) at the rate of 3—5 kg/h at 15—25°C until the pH was 7. Then the pH of the mixture was adjusted with a hydrochloric acid solution which was prepared from concentrated hydrochloric acid (1.09 kg) in ed water (0.80 kg) until the pH was 6.2—6.4. The mixture was filtered with a nutsche filter. The filter cake was transferred into a 300 L glass—lined reactor and purified water (117.00 kg) was added. The mixture was d and sampled and analyzed by HPLC until the p- toluenesulfonic acid residue of the filter cake was 50.5%. Then the mixture was ed. The filter cake was dried in the tray drier under en at 55-65°C until KFS10%. The solid and MTBE (8.81 kg) were charged into a 50 L stainless steel drum. The mixture was stirred for 1-2 h. The mixture was filtered with a 30 L stainless steel vacuum filter. The filter cake was dried in the nutsche filter at 50— 60°C. After 8 h, the solid was sampled and analyzed by KF every 4-8 h until KFSS%.
During drying, the solid was turned over and mixed every 4-6 h. 6.3 kg of product was recovered as an off-white solid at 98.07% .
In Step 4, a dry and clean 50 L flask was purged with nitrogen for 20 min. DMF (30.20 kg) was charged into the 50 L flask reactor. Then the stirrer was started. Maintaining the temperature at 15—25°C, 12394 (3.22 kg, 2.76 kg after corrected) was added into the mixture. The mixture was stirred until the solid dissolved completely. The mixture was cooled to —10 to -20°C and 1-hydroxybenzotriazole hydrate (2.10 kg) was added into the mixture at -10 to -20°C.
Then EDCI (2.41 kg) was added into the mixture in five portions at an interval of about 5—10 min. The mixture was cooled to -20 to -30°C and ASYM-111888 hem) (1.96 kg) was added into the mixture at -20 to -30°C. Then DIEA (1.77 kg) was added into the mixture at the rate of 3-4 kg/h. The mixture was heated to -25°C at the rate of 5-10°C/h. The mixture was reacted at 15-25°C. After 6-8 h, the mixture was sampled and analyzed by HPLC every 2-4 h until the content of ASYM-112394 was 52%. The e was cooled to 0—10°C and the reaction mixture was quenched with a solution which was prepared from ethyl acetate (28.80 kg) in purified water (12.80 kg) at 0-10°C. The e was extracted three times with ethyl acetate (28.80 kg). For each extraction the e was stirred for 20—30 min and settled for 20-30 min before separation. The organic phases were combined and washed twice with purified water (12.80 kg). The mixture was stirred for 20-30 min and settled for 20-30 min before separation for each time. Then the obtained organic phase was filtered through an in—Iine fluid filter. The filtrate was transferred into a 300 L glass-lined reactor. The mixture was washed twice with a 5% acetic acid solution, which was prepared from acetic acid (2.24 kg) in purified water (42.50 kg). The solution was added at the rate of 10-20 kg/h. The organic phase was washed twice with a sodium carbonate solution, which was prepared from sodium carbonate (9.41 kg) in purified water (48.00 kg). The organic phase was washed twice with a sodium de solution, which was prepared from sodium chloride (16.00 kg) in ed water (44.80 kg). The organic phase was erred into a 300 L glass—lined reactor. Anhydrous sodium sulfate (9.70 kg) was added into the e and the mixture was stirred for 2-4 h at 15-30°C. The mixture was filtered with a nutsche filter, which was pre-loaded with about 1 cm thick silica gel (7.50 kg). The filter cake was soaked and washed with ethyl acetate (14.40 kg) before filtration. The filtrates were combined and the combined filtrate was added into a 72 L flask through an in—Iine fluid . The mixture was concentrated at TS40°C under reduced pressure (PS-0.08 MPa) until 3-4 L remained. Then MTBE (4.78 kg) was added into the mixture. The e was cooled to 0-10°C for crystallization with stirring. After 1 h, the mixture was sampled and analyzed by wt% every 1-2 h until the wt% of the mother liquor was 55% or the change of wt% between consecutive samples was 51%. The e was filtered with a vacuum filter flask and the filter cake was dried in the tray drier under nitrogen at 30-40°C until KFSO.5%. 3.55 kg of product was recovered as an off-white solid at 100% purity.
The resulting 4-(5-Chloroisopropylaminopyridiny|)-1H-pyrrole carboxylic acid [1—(3—chlorophenyl)—2—hydroxyethyl]amide free base was analyzed by XRPD (. Peaks shown in are listed in Table 2, ent peaks are listed in Table 3.
Table 2: XRPD peaks observed for 4-(5-Chloroisopropylaminopyridinyl)-1H- pyrroIe—2—carboxylic acid [1 |oropheny|)—2—hydroxyethyl]amide free base.
EC) d space (A) Intensit % 9.1 :02 9690:0212 12 .0:0.2 8.869 :0178 2 .2 : 0.2 8.664 : 0.169 7 11.4:02 7.742 :0135 5 12.5:0.2 7066:0112 25 12.7:0.2 6956:0109 8 13.3 : 0.2 6.637 : 0.099 2 .2 : 0.2 5.833 : 0.076 15 .4 : 0.2 5.769 : 0.075 46 16.0 : 0.2 5.531 : 0.069 9 17.1 :02 5173:0060 3 176 : 0.2 5.038 : 0.057 8 18.2 : 0.2 4.876 : 0.053 4 18.8 : 0.2 4.723 : 0.050 2 19.2 : 0.2 4.624 : 0.048 12 19.5 : 0.2 4.556 : 0.046 100 203102 4381 1 0.043 14 205102 4.327 1 0.042 12 214102 4.145 1 0.038 44 217102 4.102 1 0.037 11 219102 4.057 1 0.037 12 231102 3.847 1 0.033 13 233102 3.812 1 0.032 25 236102 3.774 1 0.032 26 243102 3.653 1 0.030 11 252102 3.530 1 0.028 256102 3.476 1 0.027 266102 3.355 1 0.025 270102 3.297 1 0.024 277102 3.214 1 0.023 13 279102 3.191 1 0.022 1O 282102 3.159 1 0.022 287102 3.106 1 0.021 289102 3.083 1 0.021 292102 3.057 1 0.020 302102 2.957 1 0.019 14 306102 2.923 1 0.019 Table 3: Prominent XRPD peaks for 4—(5—Chloro-2—isopropylaminopyridin-4—y|)—1H- pyrrolecarboxylio acid [1 |orophenyl)-2—hydroxyethyl]amide free base. fig) d sgace (A) Intensit % 9.1 10.2 9.690 1 0212 12 12.5102 7.066 1 0.112 25 152 :02 5.833 1 0.076 15 .4 1 0.2 5.769 1 0.075 46 W0 23574 19.2 J; 0.2 4.624 1r 0.048 12 19.5 i 0.2 4.556 i 0.046 100 .3 i 0.2 4.381 i 0.043 14 .5 i 0.2 4.327 1 0.042 12 21.4i0.2 4.145 i0.038 44 21.7102 4102:0037 11 21910.2 4.057 10.037 12 23.1 i 0.2 3.847 t 0.033 13 23.3 i 0.2 3.812 1 0.032 25 23.6 i 0.2 3.774 1r 0.032 26 24.3 i 0.2 3.653 1r 0.030 11 27.7 i 0.2 3.214 t 0.023 13 27910.2 3.191 10.022 10 .2 i 0.2 2.957 1 0.019 14 FT-IR was performed on a sample of 4—(5—Chloro isopropylaminopyridinyl)-1H-pyrrole-2—carboxylic acid [1 -(3-chlorophenyl) hydroxyethyl]amide free base as described in Example 1 (. Observed peaks from are listed in Table 4.
Table 4: Observed FT-IR peaks for 4—(5—Chloro-2—isopropylaminopyridin—4-yl)—1H- pyrrolecarboxylic acid [1 -(3-chlorophenyl)hydroxyethyl]amide free base. on (cm'1) Intensity 681 0.0174 712 0.0025 748 0.0014 783 0.0058 807 0.001 827 0.0082 857 0.0045 878 0.00069 Position (cm'1) Intensity 897 0.00067 916 0.00056 932 0.0008 996 0.0004 1040 0.00074 1080 0.0069 1 101 0.00081 1 126 0.00096 1 145 0.0014 1 170 0.0027 1 197 0.001 1 1208 0.0028 1235 0.0013 1255 0.0015 1268 0.0021 1294 0.0013 1350 0.0018 1364 0.002 1385 7 1398 0.00077 1439 0.0017 1451 0.0014 1466 0.0019 1487 0.0089 1504 0.0033 1523 0.0065 1533 0.0063 1568 0.0021 1603 0.0108 1629 0.0062 2927 0.00024 2974 0.00028 3235 0.00052 3405 0.00026 Position (cm'1) Intensity DSC was performed on a sample of 4-(5-Chloro-2— isopropylaminopyridinyl)-1H-pyrrolecarboxylic acid [1 -(3-chlorophenyl)—2— hydroxyethyl]amide free base as described in Example 1 ( and showed an endotherm having an onset temperature of imately 184°C.
EXAMPLE 3A Preparation of 4-(5-Chloroisopropylaminopyridinyl)-1H-pyrrole carboxylic acid [1 -(3-chlorophenyl)hydroxyethyl]amide Form C EtOH, MeOH, iPrOH 90:5:5 4—(5—Chloro—2—isopropylaminopyridin—4—yl)—1H—pyrrole—2—carboxylic acid [1-(3-chlorophenyl)—2—hydroxyethyl]amide Form C was prepared from 4-(5-Chloro-2— isopropylaminopyridin—4—yl)—1H—pyrroIe—2—carboxylic acid [1—(3—chlorophenyI)—2— hydroxyethyl]amide free base as follows. ASYM-111935 (10.4 kg) was added to a stirred mixture of anhydrous ethanol (73.9 kg), methanol (4.1 kg) and isopropanol (4.1 kg). The mixture was heated to 70-75°C and d until all the solids dissolved.
Anhydrous HCI (37 wt%, 1.1eq) in a e of ethanol/methanol/isopropanol (90:55) was added and the mixture maintained at 70-75°C for 2 hours after the addition was completed. The mixture was then cooled to 15-25°C at a rate of 5— °C per hour and stirred at this ature until the desired polymorphic purity was d. The end point of the crystallization/polymorph conversion was determined by the absence of an XRPD peak at about 105° 26 in three successive samples.
The mixture was then filtered and washed successively with a pre- ed solution of ous l (14.8 kg), methanol (0.8 kg) and isopropanol (0.8 kg), followed by MTBE (2 x 21 kg). Avoidance of delay in the washing of the filter cake is preferable because the polymorph may be unstable in the wet filter cake in the presence of reagent alcohol and improved stability was observed after the MTBE wash has been performed. The wet filter cake was then dried in a heated filter funnel or a tray drier at 40—50°C until dry. Typical yields were about 85—90%.
EXAMPLE 3B Alternative ation of 4-(5-Chloroisopropylaminopyridinyl)-1H- pyrrolecarboxylic acid [1 -(3-chlorophenyl)hydroxyethyl]amide Form C /LNH ANH 1.Anhydrous ethanol HCI 2.Methano| ' N \ O N \ O | 3.lsopropano| [ \\ NH as / . \\ NH \./\ 7o~75°c \./\ 0' NH :‘ 0H C' 88.65%yield NH : OH Cz1Hfig|§§4oz CI CI 021235;,31402 ASYM-111935 END-523 ASYM-115985 h|oroisopropylaminopyridiny|)-1H—pyrroIe—2-carboxylic acid [1—(3—ch|oropheny|)hydroxyethyl]amide Form C was also prepared from 4-(5- Chloroisopropylaminopyridin—4-y|)-1H-pyrrolecarboxylic acid [1 -(3- chIorophenyl)—2-hydroxyethyl]amide free base as follows. A dry and clean 72 L flask was purged with nitrogen for 20 min. Anhydrous ethanol (21.35 kg) methanol (1.17 kg) and isopropanol (1.19 kg) were charged into the 72 L flask at 15—25°C and the mixture was stirred for 20-30 min. ASYM-111935 (3.01 kg) was added into the mixture and heated to 70—75°C at the rate of 15-25°C/h and stirred until the solid dissolved completely.
An alcohol / HCI solution was prepared as follows. Anhydrous ethanol (1.500 kg) methanol (0.088 kg) and isopropanol (0.087 kg) were d into a 5 L flask at 15-25°C and the mixture was stirred for 20-30 min. The mixture was bubbled with hydrogen chloride through a dip tube under stirring at 10—25°C. After 2 h, the mixture was sampled and analyzed every 2-4 h until the wt% of hydrogen chloride was 2 35%.
The alcohol / HCI solution (0.519 kg) ed above was added se into the mixture at the rate of 0.5—1.0 kg/h at 70—75°C. Seed l (0.009 kg) was added into the mixture and the alcohol / HCI solution (0.173 kg) prepared above was added into the mixture at the rate of 0.5-1.0 kg/h at 70-75°C. After on, the e was stirred for 1-2 h at 70-75°C. The mixture was cooled to 15- °C at the rate of 5—15°C/h and stirred for 4—6 h. The mixture was heated to 70— 75°C at the rate of 15-25°C/h and stirred for 8-10 h at 70-75°C. The mixture was cooled to 15-25°C at the rate of 5-15°C/h and stirred for 4—6 h. The mixture was filtered with a vacuum filter flask. The filter cake was soaked and rinsed with a solution which was prepared from anhydrous ethanol (4.25 kg) and methanol (0.24 kg) and isopropanol (0.24 kg) before filtration. The filter cake was dried in a drying room under nitrogen at 40-50°C until the ethanol residue was <0.5% and ol e was <0.3% and isopropanol residue was <0.3%. 2.89 kg of product was recovered as a white solid at 99.97% purity.
The resulting 4—(5-Chloroisopropylaminopyridin—4-yI)—1H-pyrrole carboxylic acid [1-(3-chIorophenyl)hydroxyethyl]amide Form C was analyzed by XRPD (. Peaks shown in are listed in Table 5, prominent peaks are listed in Table 6.
Table 5: XRPD peaks observed for 4—(5—Chloro-2—isopropylaminopyridin—4-yl)—1H- pyrrole—2-carboxylio acid [1-(3-chlorophenyl)hydroxyethyl]amide Form C. fie) d space (A) lntensit % 6.1 i 0.2 14.436 i 0.472 17 6.7 i 0.2 13.099 i 0.388 61 8.6 i 0.2 10.287 i 0.239 5 .8iO.2 8.196i0.152 5 11.0i0.2 803910.146 15 12.1 i0.2 7.335i0.121 15 .2 7.108i0.114 6 13.5 i 0.2 6.533 1 0.096 8 13.7 i 0.2 6.467 t 0.094 10 .2 i 0.2 5.828 i 0.076 38 16.5 i 0.2 5.363 i 0.064 18 16.9 i 0.2 5.258 i 0.062 7 17.2i0.2 5139:0059 5 17.6 i 0.2 5.023 i 0.056 59 17.9 i 0.2 4.949 t 0.055 37 18.4 i 0.2 4.818 i 0.052 32 18.7 i 0.2 4.743 i 0.050 13 19.0 i 0.2 4.671 i 0.049 4 19.2 i 0.2 4.628 i 0.048 4 19.6 i 0.2 4.529 i 0.046 14 19.9 i 0.2 4.450 i 0.044 100 .4 i 0.2 4.354 i 0.042 18 .6 i 0.2 4.318 i 0.042 28 .8 i 0.2 4.272 i 0.041 52 215102 4.122 1 0.038 28 221102 4.016 1 0.036 226102 3.935 1 0.034 28 227102 3.923 1 0.034 27 235102 3.785 1 0.032 43 240102 3.704 1 0.030 29 243102 3.664 1 0.030 12 245102 3.634 1 0.029 249102 3.573 1 0.028 56 254102 3.498 1 0.027 60 257102 3.467 1 0.027 37 260102 3.424 1 0.026 264102 3.375 1 0.025 277102 3.224 1 0.023 22 280102 3.182 1 0.022 11 283102 3.147 1 0.022 292102 3.056 1 0.020 296102 3.020 1 0.020 299102 2.983 1 0.019 28 302102 2.957 1 0.019 10 Table 6: Prominent XRPD peaks for 4-(5-ChIoroisopropylaminopyridiny|)-1H- pyrroIe-2—carboxylic acid chIorophenyl)hydr0xyethyl]amide Form C.
M EMA) Intensit % 6.1 :0.2 14.435 : 0.472 17 6.7 :02 13.099 1 0.388 61 11.0:02 8.039 1 0.146 15 12.1 :02 7.335 1 0.121 15 13.7 :02 6.467 1 0.094 1O .2 i 0.2 5.828 t 0.076 38 16.5 i 0.2 5.363 i 0.064 18 17.6 i 0.2 5.023 i 0.056 59 17.9 i 0.2 4.949 i 0.055 37 18.4 i 0.2 4.818 i 0.052 32 18.7 i 0.2 4.743 i 0.050 13 19.6 i 0.2 4.529 i 0.046 14 19.9 i 0.2 4.450 1r 0.044 100 .4 i 0.2 4.354 1 0.042 18 .6 J; 0.2 4.318 1r 0.042 28 .8 i 0.2 4.272 t 0.041 52 21.5i0.2 4.122i0.038 28 22.6 i 0.2 3.935 i 0.034 28 22.7 i 0.2 3.923 i 0.034 27 23.5 i 0.2 3.785 i 0.032 43 24.0 i 0.2 3.704 i 0.030 29 24.3 i 0.2 3.664 i 0.030 12 24.9 i 0.2 3.573 1r 0.028 56 .4 i 0.2 3.498 1 0.027 60 .7 J; 0.2 3.467 1r 0.027 37 27.7 i 0.2 3.224 t 0.023 22 28.0 i 0.2 3.182 i 0.022 11 29.9 i 0.2 2.983 i 0.019 28 .2 i 0.2 2.957 i 0.019 10 FT-IR was performed on a sample of Form C as described in Example 1 (. Observed peaks from are listed in Table 7.
Table 7: ed FT-IR peaks for 4-(5-ChIoroisopropylaminopyridinyl)—1H- pyrrole—2—carboxylic acid [1—(3—chlorophenyl)—2—hydroxyethyl]amide Form C.
WO 23574 Position (cm'1) Intensity 680 0.0389 694 0.0737 705 0.0203 723 0.0273 728 0.0245 742 0.0263 771 0.0449 785 0.0527 845 0.0479 865 0.0128 879 0.0232 922 0.0112 946 0.0275 958 0.011 985 0.0119 1000 0.0124 1076 0.0649 1107 0.0183 1129 0.0245 1141 0.0322 1177 0.018 1219 0.0554 1246 0.0238 1282 0.0279 1310 0.0342 1324 0.0179 1344 0.0144 1376 0.0239 1380 0.024 1389 0.0204 1413 0.0196 1436 0.0324 1472 0.0279 1498 0.0254 on (cm'1) Intensity 1523 0.0543 1551 0.027 1574 0.0371 1610 0.0697 1643 0.0865 2952 0.0153 2977 0.0167 3057 0.015 3178 0.0147 3229 0.0162 3294 0.0171 3369 0.0161 DSC was performed on a sample of Form C as described in Example 1 ( and showed a prominent endotherm having an onset temperature of approximately 239°C.
EXAMPLE 4 Preparation of 4-(5-Chloroisopropylaminopyridinyl)-1H-pyrrole-Z- carboxylic acid [1 -(3-chlorophenyl)hydroxyethyl]amide Form A 4-(5-Chloroisopropylaminopyridinyl)—1H-pyrrolecarboxylic acid [1-(3-chlorophenyl)—2—hydroxyethyl]amide Form C was ved in methanol at 60°C resulting in a clear solution. The sample was slow cooled from 60°C to ambient temperature followed by fast evaporation. 4-(5-Chloroisopropylaminopyridinyl)— 1H-pyrrolecarboxylic acid [1 -(3-chlorophenyl)hydroxyethyl]amide Form A was formed as white solids / needles. atively, 4-(5-Chloroisopropylaminopyridinyl)-1H-pyrrole carboxylic acid [1-(3-chlorophenyl)hydroxyethyl]amide Form C was dissolved in ethanol at 60°C resulting in a clear solution. The sample was slow cooled from 60°C to ambient temperature followed by fast evaporation. 4—(5—Chloro isopropylaminopyridinyl)-1H-pyrrole-2—carboxylic acid [1 -(3-chlorophenyl) hydroxyethyl]amide Form A was formed as white solids / needles.
Alternatively, 4-(5-Chloroisopropylaminopyridinyl)-1H-pyrrole carboxylic acid [1—(3—chlorophenyl)—2—hydroxyethyl]amide Form C was prepared as a slurry in ethanol ing in a white suspension. The ethanol slurry was maintained at ambient temperature for 7 days. 4—(5—Chloro—2—isopropylaminopyridin—4—yI)—1H— pyrrolecarboxylic acid [1-(3-chlorophenyl)hydroxyethyl]amide Form A was formed as white tiny specks.
The ing 4-(5-Chloroisopropylaminopyridinyl)-1H-pyrrole ylic acid [1—(3—chIorophenyl)—2—hydroxyethy|]amide Form A was analyzed by XRPD (. Peaks shown in are listed in Table 8, prominent peaks are listed in Table 9.
Table 8: XRPD peaks observed for 4-(5-Chloroisopropylaminopyridinyl)-1H- pyrrole—2-carboxylic acid [1—(3—chloropheny|)hydroxyethyl]amide Form A.
QC) dspace (A) Intensit % 58:02 15.175i0.521 20 .9 i 0.2 14.992 i 0.509 22 6.2 i 0.2 14.250 i 0.459 76 10510.2 841810.160 100 11.7i0.2 7.571 $0.129 6 .2 7.474i0.126 11 12.4i0.2 7.114i0.114 20 .3 i 0.2 5.772 i 0.075 7 .9 i 0.2 5.587 i 0.070 17 16.1 i 0.2 5.506 i 0.068 9 16.3 i 0.2 5.440 1 0.066 6 WO 23574 164102 5.393 1 0.065 176102 5.048 1 0.057 49 178102 4.980 1 0.056 21 187102 4.740 1 0.050 198102 4.478 1 0.045 200102 4.427 1 0.044 25 204102 4.345 1 0.042 10 207102 4.291 1 0.041 209102 4.249 1 0.040 211102 4.209 1 0.039 11 214102 4.153 1 0.038 23 219102 4.052 1 0.037 17 224102 3.963 1 0.035 82 231102 3.854 1 0.033 11 235102 3.790 1 0.032 240102 3.702 1 0.030 47 242102 3.677 1 0.030 23 249102 3.570 1 0.028 100 253102 3.523 1 0.027 19 267102 3.470 1 0.027 27 264102 3.370 1 0.025 10 269102 3.317 1 0.024 17 269102 3.307 1 0.024 16 272102 3.281 1 0.024 13 273102 3.260 1 0.023 11 278102 3.208 1 0.023 281102 3.178 1 0.022 29 285102 3.130 1 0.022 43 290102 3.082 1 0.021 298102 2.999 1 0.020 32 Table 9: Prominent XRPD peaks for 4-(5-ChIoroisopropylaminopyridinyI)-’|H- pyrroIe—2—carboxylic acid [1—(3—chIorophenyl)—2—hydroxyethyl]amide Form A.
QC) d sgace (A) Intensit % .8i0.2 15.175i0.521 20 .9 i 0.2 14.992 i 0.509 22 6.2 i 0.2 14.250 i 0.459 76 .5i0.2 8418:0160 100 11.8iO.2 7.474i0.126 11 12.4iO.2 7.114i0.114 20 .9 i 0.2 5.587 1 0.070 17 17.6 i 0.2 5.048 i 0.057 49 17.8iO.2 4.980 $0.056 21 .0 i 0.2 4.427 1 0.044 25 .4 i 0.2 4.345 i 0.042 10 21.1 i 0.2 4.209 i 0.039 11 .2 4.153 $0.038 23 21.9:02 4.052 i0.037 17 22.4 i 0.2 3.963 i 0.035 82 23.1 i 0.2 3.854 i 0.033 11 24.0 i 0.2 3.702 1 0.030 47 24.2 i 0.2 3.677 i 0.030 23 24.9 i 0.2 3.570 1- 0.028 100 .3 i 0.2 3.523 1 0.027 19 .7 i 0.2 3.470 i 0.027 27 26.4 i 0.2 3.370 i 0.025 10 26.9 i 0.2 3.317 i 0.024 17 26.9 i 0.2 3.307 i 0.024 16 27.2 i 0.2 3.281 i 0.024 13 27.3 i 0.2 3.260 t 0.023 11 28.1 i 0.2 3.178 i 0.022 29 28.5 i 0.2 3.130 i 0.022 43 29.8 i 0.2 2.999 i 0.020 32 FT-IR was performed on a sample of Form A as described in Example 1 (. Observed peaks from are listed in Table 10.
Table 10: Observed FT-IR peaks for 4-(5-ChIoroisopropylaminopyridinyl)-1H- pyrroIe—2—carboxylio acid [1—(3—chIorophenyl)—2—hydroxyethyl]amide Form A.
Position (cm'1) Intensity 679 0.0296 687 0.0661 689 0.0658 712 0.0619 729 0.0227 742 0.0202 787 0.0614 790 0.0458 827 0.04 833 0.0371 844 0.0446 868 0.0259 877 0.0224 892 0.018 920 0.014 946 0.0385 979 0.0103 1001 0.0098 1042 0.0228 1068 0.0248 1094 0.0269 1122 0.0195 on (om'1) Intensity 1163 0.0564 1192 0.0176 1215 0.0443 1237 0.0651 1284 0.0295 1309 0.0387 1329 0.0308 1345 0.0262 1383 0.0214 1394 0.0227 1428 0.0288 1452 0.0369 1462 0.0366 1471 0.0374 1500 0.0496 1537 0.0473 1573 0.064 1599 0.0412 1613 0.086 1631 0.0909 1648 0.069 1823 0.0052 2734 0.0193 2939 0.0157 2972 0.0182 3124 0.0184 3165 0.019 3250 0.0184 DSC was performed on a sample of Form A as described in Example 1 ( and showed four endothermic events: melting of water at 0°C, followed by two broad events having peak maxima at temperatures of approximately 61°C and 136°C with weight losses of 3.0% and 1.9%, respectively and, finally, an endotherm having an onset temperature of imately 201°C.
EXAMPLE 5 Preparation of hloroisopropylaminopyridinyl)-1H-pyrrole carboxylic acid [1 -(3-chlorophenyl)hydroxyethyl]amide Form D A vessel containing 4-(5-Chloro—2-isopropylaminopyridinyl)—1H— pyrrolecarboxylic acid [1-(3-chlorophenyl)hydroxyethyl]amide Form A was purged with dry nitrogen and relative ty was monitored. After about 73 minutes the relative humidity had decreased from 36.9% to 1.0%. The resulting material was analyzed and was determined to be a new form, designated Form D.
In a related experiment, a sample of 4—(5—Chloro isopropylaminopyridinyl)-1H-pyrrole-2—carboxylic acid [1 -(3-chlorophenyl) hydroxyethyl]amide Form D was, upon sorption of water, observed to be Form A.
This led to the conclusion that Forms A and D interconvert reversibly as a function of relative humidity.
A sample of 4-(5-Chloroisopropylaminopyridinyl)-1H-pyrrole carboxylic acid [1—(3—chlorophenyl)—2—hydroxyethyl]amide Form D was analyzed by XRPD (). Peaks shown in are listed in Table 11, ent peaks are listed in Table 12.
Table 11: XRPD peaks ed for 4-(5-Chloroisopropylaminopyridinyl)-1H- pyrrole—2—carboxylic acid [1—(3—chlorophenyl)—2—hydroxyethyl]amide Form D.
QC) d space (A) lntensit % 6.0 i 0.2 14.688 i 0.488 66 6.3 i 0.2 13.925 i 0.439 81 .7 i 0.2 8.247 i 0.153 50 120102 7.358 1 0.122 42 127102 6.981 1 0.110 36 156102 5.680 1 0.072 13 162102 5.479 1 0.067 12 163102 5.421 1 0.066 29 167102 5.303 1 0.063 11 179102 4.954 1 0.055 32 181102 4.908 1 0.054 100 191102 4.656 1 0.048 198102 4.480 1 0.045 199102 4.455 1 0.044 203102 4.382 1 0.043 203102 4.363 1 0.042 LwL-hto 214102 4.153 1 0.038 17 217102 4.090 1 0.037 60 222102 4.006 1 0.036 19 224102 3.968 1 0.035 228102 3.898 1 0.034 237102 3.744 1 0.031 242102 3.683 1 0.030 12 249102 3.572 1 0.028 18 255102 3.491 1 0.027 257102 3.468 1 0.027 13 269102 3.309 1 0.024 272102 3.276 1 0.024 23 273102 3.268 1 0.024 17 274102 3.258 1 0.023 29 276102 3.230 1 0.023 279102 3.193 1 0.022 281102 3.168 1 0.022 18 282102 3.159 1 0.022 14 284102 3.137 1 0.022 286102 3.121 1 0.021 11 291102 3.065 1 0.021 292102 3.055 1 0.020 294102 3.031 1 0.020 297102 3.005 1 0.020 301102 2.967 1 0.019 030-me Table 12: Prominent XRPD peaks for 4—(5—ChIoro—2—isopropylaminopyridin—4—yI)—1H— pyrrole—2—carboxylic acid [1-(3-chIorophenyI)hydroxyethyl]amide Form D.
QC) d sgace (A) it % 6.0 1 0.2 14.688 1 0.488 66 6.3 1 0.2 13.925 1 0.439 81 .7 1 0.2 8.247 1 0.153 50 12.0102 7.358 10.122 42 12.7102 6.981 10.110 36 .6 1 0.2 5.680 1 0.072 13 16.2 1 0.2 5.479 1 0.067 12 16.3 1 0.2 5.421 1 0.066 29 16.7 1 0.2 5.303 1 0.063 11 17.9 1 0.2 4.954 1 0.055 32 18.1 1 0.2 4.908 1 0.054 100 21410.2 4.15310.038 17 217 1 0.2 4.090 1 0.037 60 22.2 1 0.2 4.006 1 0.036 19 24.2 1 0.2 3.683 1 0.030 12 24.9 1 0.2 3.572 1 0.028 18 .7 1 0.2 3.468 1 0.027 13 27.2 1 0.2 3.276 1 0.024 23 27.3 i 0.2 3.268 t 0.024 17 27.4 i 0.2 3.258 i 0.023 29 28.1 i 0.2 3.168 i 0.022 18 28.2 i 0.2 3.159 i 0.022 14 28.6i0.2 3.121 i0.021 11 FT-IR was performed on a sample of Form D as bed in Example 1 (). Observed peaks from are listed in Table 13.
Table 13: Observed FT-lR peaks for 4-(5-Chloro—2-isopropylaminopyridinyl)-1H- pyrrole—2-carboxylic acid [1—(3—chlorophenyI)-2—hydroxyethyl]amide Form D.
Position (cm'1) Intensity 687 0.0579 690 0.057 698 0.0283 712 0.0567 728 0.0183 740 0.0162 745 0.0172 750 0.0147 763 0.0177 787 0.0527 791 0.0353 834 0.0372 846 0.0406 852 0.0298 868 0.0215 876 0.0185 891 0.0161 920 0.01 13 946 0.0294 979 0.0085 1001 0.0083 Position (cm'1) Intensity 1041 0.0223 1067 0.0216 1094 0.0206 1123 0.017 1163 0.0402 1194 0.0146 1215 0.0341 1239 0.0478 1284 0.0248 1309 0.0269 1329 0.0212 1346 0.0207 1382 0.0162 1394 0.0159 1451 0.0276 1471 0.0291 1500 0.0373 1537 0.0375 1574 0.045 1599 0.0292 1613 0.0585 1631 0.0652 1647 0.0542 1823 0.0044 2736 0.0129 2939 0.0107 2973 0.0115 3124 0.0113 3163 0.0111 3248 0.0109 DSC was performed on a sample of Form D as described in Example 1 () and showed erms having peak maxima at temperatures of approximately 156 and 204°C, respectively. The DSC is consistent with that of Form A, except that the first two endotherms related to the melting and loss of water are not t in the DSC trace of Form D. Thus, the DSC is consistent with the conclusion that Form D is dehydrated Form A.
EXAMPLE 6 Comparison of 4-(5-Chloroisopropylaminopyridinyl)-1H-pyrrole ylic acid [1 |orophenyl)hydroxyethyl]amide Forms A and C by Raman Spectroscopy Samples of each of 4-(5-Chloro-2—isopropylaminopyridinyl)—1H- e—2—carboxylic acid [1—(3—chlorophenyl)—2—hydroxyethyl]amide Forms A and C were ed at 60 mg/ml in a ethanolzmethanolzisopropanol (90:5:5) mixture at 24°C. Raman spectroscopy was performed on each sample and on the solvent alone as described in Example 1.
Results for a scan of wavelengths 1000 — 1600 cm'1 are shown in . A clear characteristic peak at about 1165 cm'1 was observed for Form A.
Results for a scan of wavelengths 950 — 1030 cm'1 are shown in . A characteristic peak at about 983 cm'1 was observed for Form A and a characteristic peak at about 987 cm'1 was observed for Form C.
Although illustrative embodiments of the present invention have been described herein, it should be understood that the invention is not limited to those described, and that various other changes or modifications may be made by one skilled in the art without departing from the scope or spirit of the invention.
CITED REFERENCES 1. Kohno M, Pouyssegur J (2006) Targeting the ERK signaling pathway in cancer therapy. Ann Med 38: 200—21 1. 2. Kuby, J., Immunology, 3rd Ed., W.H. Freeman & Co., New York. 3. Lee DC, Webb ML(2003) Pharmaceutical Analysis. John Wiley & Sons, Inc., New York: 255-257. 4. Peterson ML, Hickey MB, Zaworotko MJ and Almarsson O (2006) Expanding the Scope of Crystal Form Evaluation in Pharmaceutical e. J Pharm ceut Sci 9(3):317-326.
. Pierce g and Handbook, 1994-1995; Pierce Chemical 00., Rockford, Ill. 6. Remington, The Science and Practice of Pharmacy (21st Edition, Lippincott Williams and Wilkins, Philadelphia, PA. 7. The United States Pharmacopeia—National Formulary, The United States Pharmacopeial Convention, Rockville, MD.
All documents cited in this application are hereby incorporated by reference as if recited in full herein.

Claims (26)

What is d is:
1. A method of preparing a first crystalline form of a compound of a (I): comprising the steps of: (a) providing a mixture comprising the compound of formula (I) in an organic solvent; (b) adding anhydrous sodium sulfate to the mixture of step (a); (c) concentrating the mixture of step (b); (d) adding MTBE to the mixture of step (c); (e) cooling the mixture of step (d) to a temperature of between about 0°C to about 10°C to crystallize a first crystalline from of formula (I) ; and (f) filtering the mixture of step (e) to e the first crystalline form of formula
2. The method according to claim 1, wherein the first lline form of the compound of formula (I) has an X-ray powder diffraction (XRPD) pattern comprising a characteristic peak at about 19.5° 2θ.
3. The method according to claim 1, wherein the first crystalline form of the compound of formula (I) has an X-ray powder diffraction (XRPD) pattern comprising teristic peaks at about 9.1 and 19.5° 2θ.
4. The method according to claim 1, wherein the first crystalline form of the compound of formula (I) has an X-ray powder diffraction (XRPD) pattern comprising characteristic peaks at about 9.1, 15.4, 19.5, and 21.4° 2θ .
5. The method according to any one of claims 1 to 4, further comprising the steps of: (g) dissolving the first crystalline form of formula (I) from step (f) in a mixture of anhydrous ethanol, methanol, and isopropanol at a temperature of between about 70°C to about 75°C; (h) adding anhydrous HCl to the mixture of step (g); (i) g the mixture of step (h) to a temperature of between about 15°C to about 25°C at a rate of between about 5°C to about 15°C per hour to crystallize a second crystalline form of formula (I); and (j) filtering the e of step (i) to isolate the second crystalline form of formula (I).
6. The method according to claim 5, wherein the second crystalline form of the compound of formula (I) has an X-ray powder diffraction (XRPD) n comprising a characteristic peak at about 6.7° 2θ .
7. The method according to claim 5, n the second crystalline form of the compound of formula (I) has an X-ray powder ction (XRPD) n comprising characteristic peaks at about 6.7 and 11.0° 2θ .
8. The method according to claim 5, wherein the second crystalline form of the compound of formula (I) has an X-ray powder diffraction (XRPD) pattern sing characteristic peaks at about 6.7, 11.0, 17.6, and 19.9° 2θ .
9. The method according to any one of claims 1 to 4, further comprising the steps of: (g) dissolvingthe first crystalline form of formula (I) from step (f) in a mixture of anhydrous ethanol, methanol, and isopropanol at a temperature of between about 70°C to about 75°C ; (h) adding anhydrous HCl to the mixture of step (g); (i) contacting the mixture of step (h) with seed crystal; (j) cooling the mixture of step (i) to a temperature of between about 15°C to about 25°C at a rate of between about 5°C to about 15°C per hour to crystallize the second crystalline form of formula (I); and (k) filtering the mixture of step (j) to isolate the second crystalline form of formula (I).
10. The method according to claim 9, wherein the second crystalline form of the compound of formula (I) has an X-ray powder diffraction (XRPD) pattern comprising a characteristic peak at about 6.7° 2θ.
11. The method according to claim 9, wherein the second crystalline form of the compound of formula (I) has an X-ray powder diffraction (XRPD) pattern comprising characteristic peaks at about 6.7 and 11.0° 2θ.
12. The method according to claim 9, wherein the second crystalline form of the compound of formula (I) has an X-ray powder diffraction (XRPD) pattern comprising characteristic peaks at about 6.7, 11.0, 17.6, and 19.9° 2θ.
13. The method according to claim 5 or claim 9, further comprising the steps of: (l) dissolving the second crystalline form of formula (I) from step (j) or step (k) in methanol at a temperature of about 60°C; (m) slow cooling the e of step (l) to ambient ature; and (n) fast evaporating the mixture of step (m) resulting in a third crystalline form of formula (I).
14. The method according to claim 5 or claim 9, further comprising the steps of: (l) dissolving the second crystalline form of formula (I) from step (j) or step (k) in l at a ature of about 60°C; (m) slow cooling the mixture of step (l) to ambient temperature; and (n) fast evaporating the mixture of step (m) ing in a third crystalline form of formula (I).
15. The method according to claim 5 or claim 9, further comprising the steps of: (l) mixing the second crystalline form of formula (I) from step (j) or step (k) in ethanol to form a slurry; (m) maintaining the slurry of step (l) at ambient ature for 7 days, resulting in a third crystalline form of formula (I).
16. The method ing to any of claims 13 to 15, wherein the third crystalline form of the compound of formula (I) has an X-ray powder diffraction (XRPD) pattern comprising a characteristic peak at about 10.5° 2θ.
17. The method according to any of claims 13 to 15, wherein the third crystalline form of the compound of a (I) has an X-ray powder ction (XRPD) pattern comprising characteristic peaks at about 6.2 and 10.5° 2θ.
18. The method according to any of claims 13 to 15, wherein the third crystalline form of the compound of formula (I) has an X-ray powder diffraction (XRPD) pattern comprising characteristic peaks at about 6.2, 10.5, 22.4, and 28.5° 2θ.
19. The method according to claim 13 or claim 14, further comprising the steps of: (o) purging the third crystalline form of formula (I) from step (n) with dry nitrogen until relative humidity is about 1.0%, resulting in a fourth crystalline form of formula (I).
20. The method according to claim 15, further comprising the steps of: (n) purging the third crystalline form of formula (I) from step (m) with dry nitrogen until relative humidity is about 1.0%, resulting in a fourth crystalline form of formula (I).
21. The method according to claim 19, wherein the fourth crystalline form of the nd of formula (I) has an X-ray powder diffraction (XRPD) pattern sing a characteristic peak at about 10.7° 2θ.
22. The method according to claim 19, wherein the fourth crystalline form of the compound of formula (I) has an X-ray powder diffraction (XRPD) pattern comprising characteristic peaks at about 10.7 and 18.1° 2θ.
23. The method according to claim 19, wherein the fourth crystalline form of the compound of a (I) has an X-ray powder ction (XRPD) pattern comprising characteristic peaks at about 6.0, 10.7, 12.7, and 18.1° 2θ.
24. The method according to claim 20, wherein the fourth crystalline form of the compound of formula (I) has an X-ray powder diffraction (XRPD) n comprising a characteristic peak at about 10.7° 2θ.
25. The method according to claim 20, wherein the fourth crystalline form of the compound of formula (I) has an X-ray powder diffraction (XRPD) pattern comprising characteristic peaks at about 10.7 and 18.1° 2θ.
26. The method according to claim 20, wherein the fourth crystalline form of the compound of formula (I) has an X-ray powder diffraction (XRPD) pattern sing characteristic peaks at about 6.0, 10.7, 12.7, and 18.1° 2θ. mmuwwam cheem GE 1';31mm} .filgsumu; WO 23574 PCT/USZOl
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